The State of
Innovation in
Vaccines andProphylactic
Antibodies for
Infectious
Diseasesby David Thomas, CFA
and Chad Wessel
BIO INDUSTRY ANALYSIS
December 2023

About BIO
The Biotechnology Innovation Organization (BIO) is theworld’s largest trade association representing biotechnology
companies, academic institutions, state biotechnology
centers and related organizations across the United Statesand in more than 30 other nations. BIO members are
involved in the research and development of innovative
healthcare, agricultural, industrial, and environmental
biotechnology products. BIO also produces the BIO
International Convention, the world’s largest gathering of
the biotechnology industry, along with industry-leading
investor and partnering meetings held around the world.
Access BIO Industry Analysis reports here:
www.bio.org/iareports

Authors
David Thomas, CFA
Senior Vice President, Industry Research & Analysis
Biotechnology Innovation Organization (BIO)

Chad Wessel
Director, Industry Research & Policy Analysis
Biotechnology Innovation Organization (BIO)

Acknowledgements
We would like to acknowledge BIO’s Phyllis Arthur,
Emily Acker, Joel Straus, Cartier Esham, as well as
Timothy Cook, Kelly Cappio, and Kate Mevis for reviewof this report.

Vaccines and Prophylactic Antibodies
for Infectious Diseases
Introduction
Vaccines are a compelling solution to emerging and establishedinfectious disease threats. Vaccination is often cited amongthe 10 greatest public health achievements of the 20th century1— only access to safe and clean water has had a greater impact
on human health by preventing disease and extending
lifespans.2 The U.S. Centers for Disease Control and Prevention(CDC) estimate that U.S. children born between 1994 and 2021
who are vaccinated according to the recommended
immunization schedule will prevent 472 million illnesses and29.8 million hospitalizations over the course of their lifetimes.3
The overall impact on mortality reduction can be seen in Figure
1, which illustrates numerous vaccines yielding a 100%, or near
100%, reduction in the risk of death. Prior to the introductionof vaccines, these diseases caused significant morbidty andmortality. Examples include the eradication of polio and therecent reduction in deaths due to the SARS-CoV-2 pandemic.
In addition to these examples, vaccines have been shown to
reduce the risk of cancer and other longer-term diseases. For
example, the percentage of cervical lesions (precancers that
could progress to invasive cervical cancer) dropped by 40% in
women vaccinated against human papillomavirus (HPV).4

Unfortunately, not all diseases have been amenable toprevention with efficacious vaccines. For example, humanimmunodeficiency virus (HIV) vaccines have been researchedand developed for nearly 40 years with no success. Further,
tuberculosis, Streptococcus A, Schistosomiasis, Chagas, Nipah,
Lassa, MERS, Zika, Hepatitis C, Gonorrhea, Plague (Yersinia),
Salmonella, Shigella, E. coli, Klebsiella pneumoniae, Chlamydia,
Coxsackie virus, Norovirus, Chikungunya, CMV, HSV-2, EBV
and other infectious diseases with significant human burden
remain without a vaccine. Biotechnology companies today
continue to search for innovative ways to elicit an enduring
immune response for these infectious pathogens. The mostadvanced, novel pipeline candidates developed bybiopharmaceutical companies are outlined in this report.6

EXAMPLES OF VACCINE IMPACT ON MORTALITY

Reduction in Deaths Post Vaccination
0%

20%

40%

60%

Polio
Smallpox
Measles
Mumps
RubellaDiphteria
Pertussis
TetanusCovid-19
Hepatitis A
Varicella
Hepatitis B

80%

100%
100%
100%
100%
100%
100%
100%
99.7%
99.6%
90.0%
88.7%
84.3%
83.6%

Figure 1. Reduction in death due to vaccination for various diseases. Diseases with vaccination and the percent
reduction in deaths post vaccination. See footnotes for sources.5

BIO Industry Analysis

1

Executive Summary
Pipeline & Investment•

The global clinical pipeline for infectious disease vaccinesconsists of 249 active novel clinical-stage programs thatare company sponsored. There are 31 infectious diseases
represented in the clinical pipeline for which there is no
currently available approved vaccine. The clinical pipeline
has breadth, but lacks the depth likely required forsuccessful product development for many
important pathogens.

Clinical success rates have been above average for
vaccines during the period 2013-2022. With an 11%
likelihood of FDA approval (LOA) from Phase I, vaccines
outperformed non-vaccine biologics, which have a 7.6%
LOA over the same time frame. By comparison, novel
small molecules across all diseases had only 5.6% LOA.

•

Venture capital investments in global companies with
infectious disease vaccine programs totaled $6.5 billion
over the last 10 years. This represents 3.4% of total
venture capital raised for biopharmaceutical companies
during the same period. By contrast, oncology drug
development companies raised $72.6 billion over the last
decade, a 12-fold greater investment than in vaccines.
Public companies with infectious disease vaccine
programs raised $8.7 billion, $3.2 billion from IPOs and$5.5 billion from secondary offerings. $6 billion of the $8.7
billion was raised during the COVID-19 pandemic.

•

For programs against parasitic pathogens, there
are eight clinical-stage programs for malaria andschistosomiasis.

The clinical pipeline for prophylactic antibodies is small
relative to vaccines, with only 16 in clinical-stage
development. However, the antibody pipeline targets 11
different pathogens.

•

There are 10 novel combination vaccines indevelopment covering a total of 10 pathogens.

Prophylactic antibodies have been used in broad
populations to protect against seven unique pathogens.

•

In total, vaccines for 34 unique pathogens have been
approved in the U.S. or globally. Licensed vaccines utilize
a wide range of modalities: direct antigen delivery(protein, carbohydrate, pathogen inactivation andpathogen attenuation) and indirect antigen delivery(mRNA and viral vector-based vaccines).

•

For programs against viral pathogens, there are
187 clinical-stage programs. This consists of 69
SARS-CoV-2 vaccines, 84 for other RNA viruses(more than half of these for influenza, RSV, andHIV), and 34 DNA virus vaccines (half of thesetarget HPV and Varicella-Zoster).

•

For programs against bacterial pathogens, there
are 44 clinical-stage programs. Although 18 total
bacterial pathogens are targeted, more than halfof the programs target Streptococcus
pneumoniae, Mycobacterium tuberculosis,
and meningococcus.

•

•
•

•

There is a wide range of vaccine modalities in the clinicalpipeline, including 87 protein-based vaccines, (24 are partof virus-like particles (VLPs), 53 RNA-based vaccines (40mRNA and 13 saRNA), 27 recombinant viral vector-based
vaccines, 24 glyco-conjugate vaccines, 14 inactivated and
14 live attenuated viral vaccines, 12 DNA vaccines, 12
whole cell vaccines, and seven peptide vaccines.

Proposed Solutions to Expand the Depth/Breadth of the Vaccine Pipeline••

Capitalize on use of Platform Technologies: Platform
technologies can speed development of novel
approaches to improve efficacy and/or safety of vaccines,
spur investment in new technologies in disease areasthat have been difficult to tackle and help in pandemic
preparedness. The policy environment must facilitate theuse of platform technologies to spur investment in R&D
across viral families.
Expand Access to Vaccines: Given the broad benefits ofprimary prevention to individuals and society, especiallyfor persons with underlying chronic conditions,facilitating access to immunizations through bothfinancial policies and policies that increase the types ofvaccinators (for example pharmacists) will have asignificant impact on overall healthcare
outcomes and costs.
•

Rebuild Vaccine Confidence Worldwide: Combatting
vaccine misinformation and disinformation andbolstering vaccine confidence is crucial to realizing thebroadest benefits of vaccines and a stronger vaccine
infrastructure overall.

•

Evolving ACIP and NITAG Review Processes: Evaluation
and recommendation by ACIP and other NITAGs define
the size and patient utilization for the vaccine market.
This process must adapt to the changing vaccine
landscape and create a predictable review environmentthat encourages increased investment in the space.

2

BIO Industry Analysis

Methodology
Part I of this report focuses on vaccine innovation and successat the clinical stage, as well as funding of companies with leadvaccine programs. Part II focuses on prophylactic antibodies
in clinical trials. For context on modalities and disease areas ofunmet need, a brief summary of approved vaccines andprophylactic antibodies is provided prior to the discussion. A
more detailed description of previously licensed vaccine
technologies is provided in the Appendix. This report does notcontain data or discussion on other important topics related
to vaccines including: storage, distribution, clinical safety andefficacy data, real-world evidence, pricing, or global
market access.

The initial sources for clinical candidates are the Biomedtracker
and Pharmaprojects databases, with subsequent details andupdates from company websites and peer-reviewed articles.
For international vaccine approvals, the EvaluatePharma
database was used as a primary resource. The COVID-19
pipeline data is based on the Biotechnology Innovation
Organization (BIO) COVID tracker (www.bio.org/iareports),
which relies on multiple sources including Biomedtracker
and Biocentury.

List of Figures and Charts
Intro
Figure 1. Vaccine Impact on Lives .........................................................................................................1
Figure 2. Historical Timeline of Vaccine Progress ......................................................................... 5
Figure 3. Approved Vaccines (Modalities, Diseases, Manufacturing) ................................. 6

Part 1. Vaccines
Figure 4. Clinical Pipeline for all infectious disease vaccines................................................... 8
Figure 5. Clinical Pipeline for RNA viruses........................................................................................ 9
Figure 6. Clinical Pipeline for DNA viruses...................................................................................... 12
Figure 7. Clinical Pipeline for Bacteria............................................................................................... 15
Figure 8. Clinical Pipeline for Parasites..............................................................................................17
Figure 9. Clinical Pipeline for Combination vaccines................................................................. 18
Figure 10. Probability of Success for Vaccines ..............................................................................20
Figure 11. Private Investment into Vaccines Companies.......................................................... 21

Part II. Prophylactic Antibodies
Figure 12. History of Prophylactic Antibodies...............................................................................22
Figure 13. Clinical Pipeline for Prophylactic Antibodies............................................................23

BIO Industry Analysis

3Part I. Vaccines
History of Vaccines Approved for Human Prophylaxis
Vaccination utilizes a component of a pathogen or an intact
pathogen (live and inactive), to actively train the immune
system for defensive action against a fully infectious version
of a pathogen.7 This is distinct from variolation, used prior to
the 19th century, where limited exposure to the infectious
pathogen itself was used.8 Although the first true vaccine used
in a broad population originated in the 1790s, this was by nomeans a purified vaccine that would classify as an approvablevaccine candidate today. Early vaccines were crude mixturesof pathogen variants and often came with contamination,
mixed strains, and reproducibility issues. In the second half ofthe 20th century, progress in biotechnology allowed for thedevelopment of purified vaccines with high reproducibility
using clonal strains or recombinant antigens. The first two
decades of the 21st century have led to even greater innovation,with new modalities, higher quality manufacturing, and broader
applicability.

TIMELINE OF APPROVED VACCINESAGAINST INFECTIOUS DISEASESFirst Broad
DiseaseUsage

Pathogen Type

1800s

Smallpox

DNA virus

1800s

Cholerabacteria

1910s

RabiesRNA virus

1920s

Tuberculosis (TB)

mycobacteria

Diphtheria infection

bacteria

Yellow fever

RNA virus

Tetanusbacteria

Whooping Coughbacteria

Infleunza (Flu)RNA virus

Polio

RNA virus

Measles

RNA virus

Mumps

RNA virus

RubellaRNA virus

Anthrax

bacteria

Adenovirus

DNA virus

Tick-borne Encephalitis

RNA virus

Pneumococcal Disease

bacteria

Hepatitis B

DNA virus

H. Influenza

bacteria

Typhoid Feverbacteria

Japanese Encephalitis

RNA virus

Chickenpox

DNA virus

Hepatitis A

RNA virus

Lyme Disease (withdrawn)

bacteria

Meningococcal Disease

bacteria

ShinglesDNA virus

Rotaviral enteritis

RNA virus

HPV

DNA virus

Dengue Fever

RNA virus

Hand, Foot, Mouth Disease

RNA virus

Ebola

RNA virus

Covid-19

RNA virus

Malaria

Parasite

RSV

RNA virus

1930s

1940s
1950s

Figure 2 lists the breadth of pathogens for which a vaccine
license has been granted and used in a large population either
in the U.S. or abroad since the 1800s.

1960s

Figure 3 illustrates the technologies used to achieve thesevaccine approvals for human use.

1970s

In the Appendix, we expand on the history of approved
vaccines and prophylactic antibodies in further detail. Thishistorical context was used to assess the novelty of the current
pipeline, with a focus on the primary antigen source,
technology type, and production methods (with less emphasison adjuvants, preservatives, dosages, or intended populations).

1980s

1990s

2000s

2010s

2020s

Figure 2. List of diseases for which vaccines have beendeveloped and approved by a government agency. The
order is based on the time period of first broad use (notyear of discovery or clinical trials). The Lyme diseasevaccine was only marketed 1998-2001 and is included forhistorical purposes and assessment of current
pipeline novelty.

4

BIO Industry Analysis

TYPES OF INFECTIOUS DISEASE VACCINES
Type

ExamplesLive Attenuated Pathogen

Measles, Mumps, Rubella, Smallpox,
Yellow Fever, Chickenpox, Influenza,
Rotavirus, Dengue

Inactivated Pathogen

Polio, Rabies, Influenza, TBE,
JEV, Enterovirus, COVID-19

Recombinant Viral Vector, Replicating

Ebola

Recombinant Viral Vector, Nonreplicating

COVID-19 (EUA)mRNA

COVID-19

Purified Antigen Protein

Influenza, Diptheria, Pertussis, Tetanus, Anthrax, Influenza, COVID-19,
RSV

Protein-VLP(Virus Like Particle)

Meningococcus Group B, Shingles,
Hepatitis B, HPV, Malaria, COVID-19

Carbohydrate-Protein Conjugate (glyco-conjugate)

Pneumococcal, Hemophilus Influenza (Hib)

Capsid Carbohydrate

Pneumococcal

Live Attenuated Bacteria

Tuberculosis (BCG), Cholera

Inactivated Bacteria[Typhoid Fever]

Illustration

Cell

Carbohydrate

Protein

Nucleic
Acid

Viral

Class

Figure 3. Types of vaccines that have been approved historically. Examples given are not an exhaustive list. Typhoid
fever inactivated whole Salmonella Typhi cell is no longer licensed, but rather an extraction of polysaccharides from
Salmonella Typhi cells.

BIO Industry Analysis

5Current Novel Clinical Pipeline for Vaccines
The current company-sponsored clinical pipeline for infectious
disease vaccines worldwide contains 249 novel clinicalprograms based on analysis of the Biomedtracker andPharmaProjects databases.9 There are 31 infectious diseases
represented in the clinical pipeline for which there is no
currently available approved vaccine.
As shown in Figure 4, there are ongoing vaccine programs for
RNA viruses, DNA viruses, bacteria, and parasitic pathogens.
RNA viruses make up the largest group with 153 clinicalprograms (61.4% of all vaccine programs). As there were far
more SARS-CoV-2 vaccine programs compared to otherindications, SARS-CoV-2 RNA virus programs are grouped
separately from the other RNA virus vaccines in Figure 4. After
109 suspended programs over the last few years, there are now
69 ongoing company-sponsored clinical programs for SARSCoV-2, accounting for 27% of all vaccine programs.10 Bacterial
programs rank second by pathogen group after RNA viruses,with 44 programs (16.5% of all vaccine clinical programs). DNA
virus vaccines have a total of 34 clinical-stage programs (13.7%of all vaccine clinical programs). There are 8 parasitic clinicalstage vaccine programs, most of these for malaria. Lastly, 10
vaccine programs are combination products with first-in-classantigenic approaches.

Clinical trial phases of the vaccine pipeline are also shown in
Figure 4. Phase I has the highest number of programs with 119
clinical programs or 48% of the total vaccine pipeline. Fewer
programs are found in Phase II, with 85 comprising 34% of thepipeline. This is the opposite proportion than what is seen in
the overall industry pipeline (n=7,111 clinical programs), wheremore programs are in Phase II (49%) than in Phase I (33%). Latestage trial status percentages mirror the overall industry
pipeline composition: Vaccine Phase III and BLA clinicalprograms make up 16% and 2%, respectively.11
In terms of the types of pathogens targeted by Phase, thedistribution is similar across Phases I-III except that parasitic
va cc i n e s a n d n ew co m b i n at i o n va cc i n e s a re i n
Phase I and II only.
The pipeline within each pathogen group, by individual
pathogen species, is described below. Each group has a
breakdown by phase and a breakdown by modality of thevaccine approach.

COMPANY-SPONSORED GLOBAL CLINICAL PIPELINE FOR NOVEL VACCINES

Pathogen Type

Phase I

Phase II

Phase III

BLA

Total

Non-CoV-2 RNA viruses

49

22

10

3

84

SARS-CoV-2 RNA virus

32

23

14

0

69

DNA viruses

14

14

6

0

34

Bacteria

12

20

11

1

44

Parasites

4

4

0

0

8

Multiple Pathogen Types

8

2

0

0

10

Total

119

85

41

4

249

Figure 4. The company-sponsored global vaccine clinical pipeline by pathogen type (top) and phase (bottom) as of July
2023. Only novel vaccines for infectious disease are included.

6

BIO Industry Analysis

Vaccine Clinical Pipeline for RNA Virus Pathogens
For the 153 company-sponsored clinical programs for RNA
viruses worldwide, three are in registration-stage for approval,
24 are in Phase III, 45 in Phase II, and 81 in Phase I. There are 18
different pathogens being targeted in the vaccine pipeline aslisted in Figure 5. The types of programs and modalities withineach will be described below.
COVID-19 vaccine pipeline (Vaccine types: protein, proteinVLP, conjugate, peptide, mRNA, saRNA, viral, DNA, recombinantbacteria, recombinant human cell)
Although there are now 39 vaccines authorized or approved
for COVID-19 worldwide, there is still robust activity with 69
COVID-19 vaccines in the clinical pipeline, comprising a wide
range of modalities. Most of these vaccines are now indevelopment as updated versions, targeting newer variants
or for pan-coronavirus protection.
Protein-based vaccines outnumber all other COVID-19 vaccine
types with 20 programs. Of these 11 are in Phase I, 6 are in Phase
II, and 3 in Phase III development. All but one of the proteinbased vaccines are targeting the spike protein of COVID-19. Oneof the Phase I programs targets multiple epitopes, however, it
is not disclosed which ones. The majority (12) of the proteinbased vaccines are manufactured using mammalian cells, whileothers use insect (2), plant (1), or fungal (1) cells (four of theprotein programs do not disclose expression systems for
manufacturing).
mRNA programs have the second highest number of clinicalprograms with 13. Of these 13 programs, seven are in Phase I,
five are in Phase II, and one is in Phase III. All but one of themRNA vaccine programs codes for the spike protein, with one
program designed with a non-spike protein that is
not disclosed.
The third largest group of COVID-19 clinical-stage vaccine
programs are the non-replicating recombinant viral-vector
vaccines. Four of the programs are in Phase I, three are in Phase
II, and three are in Phase III. Of the 10 programs, five use an
adenovirus vector as the backbone for engineering, two of
which are single cycle adenoviruses, one an adenovirus 5
vector, one a gorilla adenovirus, and one is undisclosed. Twoother programs use the Newcastle virus (NDV) vectors, anotheruses a Parainfluenza virus 5 (PIV5) vector, one is derived fromthe human respiratory syncytial virus (RSV), and the final usesa modified vaccinia Ankara vector (MVA). All 10 of these
programs are designed to express the spike protein while the
M VA p r o g r a m a l s o e n c o d e s t h e n u c l e o c a p s i dprotein of SARS-CoV2.
The fourth largest group of COVID-19 clinical-stage vaccine
programs are the DNA-based vaccines with 7 programs. All these
DNA-based vaccines use DNA plasmids, with four of themBIO Industry Analysis

targeting the spike protein while the other three do notdisclose the target.
The next largest group is self-amplifying RNA (saRNA) vaccineswith six programs. For these programs, two are in Phase I, three
are in Phase II, and one is in Phase III. All six programs target
the spike protein, but one also targets other T-cell epitopest h a t a re n o t d i s c l o s e d , a n d a n o t h e r a l s o t a rg e t s
the nucleocapsid.
The Virus-like particles (VLP) modality comes next with fiveprograms. Two of the VLP programs are in Phase I, two are in
Phase II, and one is in Phase III. All six programs target
the spike protein.
The remaining programs include two peptide-based vaccines,
one each in Phase I and Phase III; two inactivated viral vaccineswith one each in Phase II and Phase III; one live attenuatedviral vaccine in Phase III; one gene edited bacteria-based
vaccine in Phase I; one semi-synthetic glycoconjugate vaccine
in Phase I; and one recombinant human cell vaccine in PhaseII that is based off dendritic cells.
Influenza vaccine pipeline (Vaccine types: protein, proteinVLP, mRNA, viral)
Influenza vaccines in the pipeline are separated into three different
indications: seasonal, universal, and pandemic. Seasonal influenza
vaccines work to address the common forms of influenza that
follow a seasonal epidemic of the disease. These vaccines may
target either Influenza A or B viruses or both. Universal Influenza
vaccines aim to be effective against all types of influenza,
regardless of strain, without the need to modify the vaccine ona seasonal basis. Pandemic influenza vaccines are vaccines that
address new and different influenza strains that could infect alarge amount of people causing a pandemic. Influenza A viruses
are currently the only influenza viruses that are known tocause pandemics.
Of the 29 influenza vaccines currently in clinical development,over half of the vaccines are seasonal influenza. Thirteen of theseasonal vaccines are utilizing RNA technologies such as mRNAand saRNA. Two are protein and protein-VLP based, a third isan inactivated virus, and a fourth seasonal vaccine candidate
is a live attenuated H1N1 strain.
For the remaining 12 influenza vaccines, seven are universal
influenza vaccines and five pandemic influenza vaccines, all
but two of the vaccines utilize modalities commonly seen invaccines approved today. The universal influenza candidate
vaccines include an HA antigen VLP, nucleoprotein, twoattenuated influenza virus strains (made by deleting Ns1 or M2
genes), self-amplifying RNA, and a peptide vaccine.

7

COMPANY-SPONSORED GLOBAL CLINICAL PIPELINE FOR RNA VIRUS PATHOGENSSARS-CoV-2

32

23

14

0

69

Influenza - Seasonal

12

1

3

1

17

Influenza - Universal

5

2

0

0

7

Influenza - Pandemic

2

3

0

0

5

RSV

6

3

2

0

11

HIV

6

2

0

0

8

Norovirus

1

5

0

0

6

Dengue

3

1

1

0

5

Rotavirus

1

1

2

0

4

Zika

2

1

0

0

3

Chikungunya

0

1

1

1

3

Nipah Virus

3

0

0

0

3

Ebola

1

1

0

0

2

Rabies

1

0

1

0

2

EEV

2

0

0

0

2

Lassa Virus

2

0

0

0

2

Coxsackie virus

1

0

0

0

1

Enterovirus

0

0

0

1

1

Yellow Fever

0

1

0

0

1

West Nile Virus

1

0

0

0

1

Total

81

45

24

3

153

10

0

7

1

1

69

6

1

0

0

0

0

0

0

17

1

0

3

0

0

0

0

0

7

0

0

2

0

0

0

0

0

0

5

2

0

0

3

0

1

0

0

0

11

0

2

0

1

0

2

0

2

0

0

8

0

0

0

0

0

2

0

0

0

0

6

0

1

0

0

0

3

0

0

0

0

0

5

1

0

0

0

0

1

1

0

0

0

0

0

4

1

0

0

0

1

0

1

0

0

0

0

0

0

3

0

1

0

0

0

0

1

1

0

0

0

0

0

3

0

0

1

0

1

0

0

0

0

1

0

0

0

3

Nipah Virus

0

0

0

0

0

0

0

0

1

0

1

0

0

2

Rabies

0

0

0

0

1

0

1

0

0

0

0

0

0

2

EEV

0

1

0

0

0

0

0

0

1

0

0

0

0

2

Lassa Virus

0

0

0

0

0

0

0

0

0

2

0

0

0

2

Coxsackie virus

0

0

0

0

0

0

1

0

0

0

0

0

0

1

Enterovirus

0

0

0

0

0

0

1

0

0

0

0

0

0

1

Yellow Fever

0

0

0

0

0

0

1

0

0

0

0

0

0

1

West Nile Virus

0

0

0

1

0

0

0

0

0

0

0

0

0

1

Total

32

16

2

5

28

13

13

12

16

4

10

1

1

153

5

1

Influenza - Seasonal

1

1

0

Influenza - Universal

1

1

0

Influenza - Pandemic

3

0

RSV

2

HIV
Norovirus

mRNA

20

peptideSARS-CoV-2

2

13

0

8

1

0

0

0

3

0

0

1

0

0

1

3

0

Dengue10Rotavirus

1

Zika
Chikungunya
Ebola

human cell(recombinant)bacteria(recombinant)1

carbohydrateprotein

2

protein
VLP

6

RNA virus vaccines

Protein

DNA

Total

rViral (replicating)BLArViral(non-replicating)Phase III

Viral (attenuated)

Phase II

Viral (inactivated)

Phase IsaRNA

RNA virus vaccines

Total

Figure 5. The company-sponsored global clinical pipeline for novel RNA virus vaccines. Top: pathogen targets andphase of program. Bottom: pathogen target and modality of vaccine.

8

BIO Industry Analysis

The five pandemic influenza vaccine clinical candidates target
H5N1, H5N6, H7N1, H7N9, and one for all H7 strains. Three ofthese are protein based and use the HA antigen of ther e s p e c t i v e i n fl u e n z a s t r a i n . Tw o p r o g r a m s u s einactivated viral strains.
RSV vaccine pipeline (Vaccine types: protein, protein-VLP,
attenuated virus, recombinant viral vector)
On the heels of the two recent vaccine approvals for RSV as
described in Appendix I, there are 12 other candidates in clinical
trials - six are in Phase I, three in Phase II, and three in Phase III.
Protein-based vaccines account for five of the 11 RSV vaccines
in clinical development. Three of the five are protein-based
vaccines that use VLPs to display the antigenic portion of theprotein. One is a synthetic VLP displaying epitopes for RSV
F-protein site II in Phase I, and the other two have VLP
displaying the pre-fusion F proteins (similar to the approved
vaccine protein conformation). The other two are pure protein
vaccines being developed ex-U.S. In China there is an RSV G
protein subunit vaccine (purified from E. coli) in Phase II, andthe other, in Phase II in Japan, uses an undisclosed RSV
protein antigen.
Two mRNA programs for RSV are in Phase II and III. The Phase
III codes for the prefusion F protein, and the Phase II geneproduct has not been disclosed (although it is also likely someversion of the F protein)Six vaccines are in clinical development for norovirus. The mostadvanced are in Phase II, of which there are five, and one
is in Phase I.
The Phase I program is testing a plant-based protein-VLP
vaccine that contains capsid proteins for GI.4 and GII.4
noroviruses. There are two Phase II programs in China: a capsid
protein vaccine for GI.1, GII.4 noroviruses using the yeast
Hansenula Polymorpha for production and a quadrivalent
protein-VLP norovirus vaccine using the yeast Pichia pastoris.
There is another purified protein-vaccine in Phase II with nodisclosed details on antigen or source of production.
There are two recombinant nonreplicating viral vaccines inPhase II. The first uses an Ad5 vector to make capsid VP1antigens for G1.1-NN and GII.4-NS.
D e n g u e v a c c i n e p i p e l i n e ( Va c c i n e t y p e s : l i v eattenuated; peptide)
There are five Dengue vaccines in the clinical pipeline in Phase
I and II. Three are live attenuated virus vaccines potentiallyeffective against all four serotypes. The other two are peptide
vaccines with one vaccine containing dengue protein
fragments and the other composed of four salivary peptides
isolated from Anopheles gambiae (mosquito) salivary glands.
Z i ka va cc i n e p i p e l i n e ( Va c c i n e t y p e s : m R N A ,inactivated, peptide)

There are four viral vaccines for RSV in clinical development.
Three programs are early-stage and use various genetic
mutations to achieve attenuation of RSV. The last is arecombinant vector-based vaccine using a PIV5 (canine
parainfluenza virus) expressing full length F protein (in Phase I).

Of the three Zika vaccine candidates, the most advanced is anmRNA vaccine in Phase II. The other candidates are in Phase
I. One is an inactivated Zika virus, and the other is composedof four salivary peptides isolated from Anopheles gambiae
salivary glands.

Furthermore, there are additional combination vaccines
containing RSV in development that will be described below
in the section on novel combination vaccines.

Chikungunya vaccine pipeline (Vaccine types: live
attenuated, protein-VLP)

HIV vaccine pipeline (Vaccine types: protein, DNA, inactivatedvirus, recombinant viral vector)
The HIV clinical vaccine pipeline includes eight vaccine
candidates, six of which are in Phase I and two in Phase II. Twoof the HIV vaccines are DNA-based (using various combinationsof g120, gp140, and gag) and two are mRNA-based. Two
vaccines are recombinant viral vectors and one is inactivatedHIV virus. There is one protein fusion vaccine in Phase I
containing the HIV antigenic protein bound to a CD40 antibody.
Norovirus vaccine pipeline (Vaccine types: protein;recombinant viral non-replicating)

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There is a live attenuated Chikungunya vaccine in registration
with regulatory authorities in the U.S. and Canada. There is alsoa Phase III VLP vaccine composed of the E1, E2, and capsid
proteins of the CHIKV (strain 37997).
Nipah vaccine pipeline (Vaccine types: mRNA)
There is a Phase I mRNA Nipah vaccine encoding a secreted
prefusion F protein linked to G monomer of Malaysianstrain NiV.
Rabies (Vaccine types: mRNA)
There is an mRNA-based vaccine encoding the rabies virus
glycoprotein RABV-G currently in an open-label, doseescalation Phase 1.

9Equine Encephalitis Virus (EEV) vaccine pipeline (Vaccine
types: recombinant virus, non-replicating)
A recombinant MVA-BN vector expressing antigens from all
three equine encephalitis viruses: western, eastern and
Venezuelan is in Phase I.
Lassa vaccine pipeline (Vaccine types: recombinantvirus, replicating)A replicating recombinant vesicular stomatitis virus (VSV)
expressing the Lassa virus surface glycoprotein is in Phase I.
Coxsackie vaccine pipeline (Vaccine types: inactivated)
There is one “polyvalent” vaccine for Hand, Foot, Mouth Disease(caused by Coxsackie virus infection) in Phase I. There is also a
combination vaccine discussed below that covers
coxsackievirus A16 (CVA16) and enterovirus 71 (EV71).
Yellow Fever (YF) vaccine pipeline (Vaccine types:
inactivated virus)
There is a serum-free Vero (African green monkey kidney) cell
derived yellow fever vaccine in Phase II. This is differentiatedfrom the approved yellow fever viral vaccine which ispropagated in chicken eggs.
We st N i l e V i r u s ( W N V ) va cc i n e p i p e l i n e(Vaccine type: peptide)
There is only one clinical-stage vaccine for West Nile Virus. This
Phase I vaccine is composed of four salivary peptides isolated
from mosquito Anopheles gambiae salivary glands.

10

BIO Industry Analysis

Vaccine Clinical Pipeline for Bacterial Pathogens
For the company-sponsored clinical pipeline for bacterial
vaccines summarized in Figure 6, there are 44 clinical-stage
programs in total with more than half of those for
Streptococcus pneumoniae (14 programs), Shigella (5),tuberculosis (4), and Meningococcus (3). In terms of phases
there are 12 in Phase I, 20 in Phase II, 11 in phase III, and only
one under BLA review. The majority (80%) of the bacterial
vaccines are protein or protein carbohydrate conjugates.

I fusion protein of four Mb antigens (Rv2608, Rv3619, Rv3620,
and Rv1813), 2) a Phase II fusion protein of three Mb antigens(85B, ESAT-6 and Rv2660c), and 3) a Phase II made of individual
Mb proteins 85B, ESAT6.

Streptococcus pneumoniae (pneumococcal disease) vaccine
pipeline (Vaccine types: inactivated bacteria; protein;carbohydrate-protein conjugate)

Meningococcal vaccine pipeline (Vaccine types: carbohydrateprotein conjugate)

Of the targeted bacterial pathogens, Streptococcus
pneumoniae (pneumococcus) has the most clinical-stage
programs in development. Six of those are in Phase I, five arein Phase II, and three are in Phase III. (The pipeline for
Streptococcus agalactiae, or group B streptococcus, isdiscussed separately in a later section).
For the early-stage pneumococcal vaccine candidates (Phase
I or II), there is one bacterial vaccine, two protein-based andseven protein-conjugate vaccines. The bacterial vaccine uses
an engineered pneumococcal strain lacking capsularpolysaccharides and inactivated using gamma irradiation. This
inactivation method has the advantage of maintaining thestructures of the surface protein antigens. One protein-based
vaccine candidate is serotype independent, offering an
advantage over other serotype specific vaccines as there are
more than 100 serotypes. Other early-stage candidates arecarbohydrate-protein conjugate vaccines and include vaccines
developed mostly outside the U.S. and contain different
valences (13, 15, 24, and 25) and different serotypes. Twocandidates stand out from the others from a technologicalstandpoint. One utilizes non-native amino acids as conjugationanchors for precise conjugation of saccharides to carrier
proteins. The other conjugation technique uses biotin-labeledpolysaccharides that bind avidin-like proteins fused toantigen proteins.
For late-stage vaccines (Phase III or BLA), the 21-valentcarbohydrate-protein conjugate vaccine uses conjugation with
CRM197, but with polysaccharides not included in any currently
licensed pneumococcal vaccines, (15A, 15C, 16F, 23A, 23B, 24F,
31, and 35B).12 Another vaccine in Phase III utilizes two carrier
proteins instead of one (CRM197 and tetanus toxoid), which
may offer advantages over using a single carrier protein.
Tuberculosis (TB) vaccine pipeline (Vaccine types: live
attenuated bacteria; protein)
There are four candidate vaccines in clinical development for
TB. Three of these are protein based and one is a live attenuatedbacteria vaccine. The protein vaccines for TB include: 1) a Phase

BIO Industry Analysis

The live attenuated vaccine is in Phase III. It is similar to the
BCG vaccine described previously but uses an engineered Mb
mycobacteria with deletions of two virulence factors genes.

There are three novel meningococcal carbohydrate-protein
conjugate vaccines in the pipeline. Two of them are pentavalentvaccines with one containing the A, C, Y, W-135, X antigens andthe other A, B, C, Y, and W antigens, in Phase II and III. A thirdis in Phase II with an undisclosed number ofcomponent antigens.
Clostridium difficile (C. diff) vaccine pipeline (Vaccine types:
live attenuated bacteria; protein)
There are two Clostridium vaccines in clinical development.
One is a protein vaccine in Phase I with very little specifics
disclosed beyond that it is adjuvanted. The other is a Phase III
live attenuated Clostridium difficile bacteria with deletions of
toxin genes tcdA and tcdB.
E. coli vaccine pipeline (Vaccine types: inactivated bacteria;carbohydrate-protein conjugate)
There are two vaccines in clinical development for E. coli. One
vaccine, in Phase II, contains four inactivated E. coli strains overexpressing CFA/I, CS3, CS5 or CS6. In addition, it contains afusion protein of enterotoxin B subunit (LTB) and CTB-subunit,
and a dmLT adjuvant. In Phase III is a 9-valent carbohydrateprotein conjugate vaccine for ExPEC (Extraintestinal Pathogenic
Escherichia Coli).
Salmonella vaccine pipeline (Vaccine types: protein-VLP;
carbohydrate-protein conjugate)
There are two clinical-stage vaccine candidates for Salmonella.
One is in Phase I and contains outer membrane vesicle (OMV)
antigens for both S. typhimurium and S. enteritidis. The otheris a carbohydrate-protein conjugate vaccine in Phase II.
Shigella vaccine pipeline (Vaccine types: carbohydrateprotein conjugate)
Many recent vaccine programs for Shigella have beensuspended recently. This is in part due to the fact that there
are four species and many serotypes of Shigella.13

11

COMPANY-SPONSORED GLOBAL CLINICAL PIPELINE FOR BACTERIAL VACCINES
Bacterial vaccines
Streptococcus pneumoniae
TB

Phase I

Phase II

Phase III

BLA

Total

6

5

3

0

14

1

2

1

0

4

0

2

1

0

3

Shigella

1

3

1

0

5

E. coli

0

1

1

0

2

Clostridium difficile

1

0

1

0

2

Group B Streptococcus

0

2

0

0

2

Salmonella

1

1

0

0

2

Bacterial - Urinary

0

0

0

1

1

Cholera

0

0

1

0

1

Staphylococcus

0

0

1

0

1

Lyme (Borrelia)

0

0

1

0

1

Plague (Yersenia)

0

1

0

0

1

Anthrax

0

1

0

0

1

Pertussis

0

1

0

0

1

Gonorrhea (Neisseria)

0

1

0

0

1

Klebsiella pneumoniae

1

0

0

0

1

Chlamydia

1

0

0

0

1

Total

12

20

11

1

44

Bacterial vaccines

Proteinprotein
VLP

carbohydrateproteinbacteria(attenuated)bacteria(inactivated)

Total

Meningococcus

Streptococcus pneumoniae

2

0

11

0

1

14

TB

3

0

0

1

0

4

Meningococcus

0

0

3

0

0

3

Shigella

0

0

4

1

0

5

E. coli

0

0

1

0

1

2

Clostridium difficile

1

0

0

1

0

2

Group B Streptococcus

1

0

1

0

0

2

Salmonella

1

0

1

0

0

2

Bacterial - Urinary

0

0

0

0

1

1

Cholera

0

0

0

0

1

1

Staphylococcus

1

0

0

0

0

1

Lyme (Borrelia)

1

0

0

0

0

1

Plague (Yersenia)

1

0

0

0

0

1

Anthrax

1

0

0

0

0

1

Pertussis

0

0

0

1

0

1

Gonorrhea (Neisseria)

0

1

0

0

0

1

Klebsiella pneumoniae

0

0

1

0

0

1

Chlamydia

1

0

0

0

0

1

Total

13

1

22

4

4

44

Figure 6. The company-sponsored global clinical pipeline for novel bacterial vaccines.
Top: pathogen targets and phase of program. Bottom: pathogen targets and modality of vaccine.

12

BIO Industry Analysis

There are five clinical-stage vaccine candidates for Shigella. One
is a Phase I genetically modified non-invasive Shigella strain thatlacks the bacterial surface coat comprised of dominant sugar
antigens. Three others are in Phase II, one being a carbohydrateprotein conjugate for Shigella dysenteriae, another acarbohydrate-protein conjugate for Shigella flexneri 2a, and thethird a quadrivalent carbohydrate-protein of four undisclosed
Shigella bacterial strains. Lastly, there is a Phase III carbohydrateprotein conjugate candidate for both Shigella flexneri and
Shigella sonnei.
Group B Streptococcus vaccine pipeline (Vaccine types:
carbohydrate-protein conjugate)
Unlike the large clinical pipeline for S. pneumoniae, S. agalactiae(Group B Streptococcus) has only two novel vaccine candidates.
One is a fusion protein vaccine in Phase II consisting of AlpCNRibN and Alp1N-Alp2/3N. The other is a hexavalent carbohydrateprotein conjugate in Phase II.
Anthrax vaccine pipeline (Vaccine type: protein)
Aside from new adjuvants for existing vaccines, there is only
one clinical candidate for Anthrax. This Phase II candidate is a
protein vaccine with purified protective antigen recombinantly
produced in Bacillus brevis. As described above, the approved
BioThrax® (Anthrax Vaccine Adsorbed) contains cell-free filtrate(which contain PA and other proteins) from Bacillus anthracis.
P e r t u s s i s v a c c i n e p i p e l i n e ( Va c c i n e t y p e : l i v e attenuated bacteria)
There is one vaccine candidate in human trials for protection
against B. pertussis infection. It is a live-attenuated bacterial
vaccine in Phase II.

It is composed of four inactivated bacteria strains: Escherichia
coli; Klebsiella pneumoniae; Proteus vulgaris; andEnterococcus faecalis.
G o n o r r h e a ( Ne i sse r i a) va cc i n e p i p e l i n e ( Va cc i n e
type: protein-VLP)
One protein vaccine, derived from the outer membrane vesicles
of Neisseria, is in Phase I for Gonorrhea.
Chlamydia vaccine pipeline (Vaccine type: protein)
There is one vaccine candidate in Phase I for Chlamydia thatu s e s a re co m b i n a n t l y ex p re s s e d C T H 5 2 2 p ro t e i nsubunit as antigen.
Staphylococcus vaccine pipeline (Vaccine type: protein)
There is one protein-based Staphylococcus aureus vaccine
being developed. This Phase III candidate contains five Staphproteins purified from E. coli.14
Plague (Yersinia) vaccine pipeline (Vaccine type: protein)
A fusion protein, Yersinia F1-V, is in Phase II studies forprotection against Plague.
Lyme Disease vaccine pipeline (Vaccine type: protein)
The single clinical-stage Lyme diseases vaccine is a proteinbased vaccine in Phase III. The withdrawn marketed vaccine
for Lyme (LYMERix®), mentioned previously in Figure 2, wasalso a purified OspA protein vaccine. The main difference isthat the new candidate is multivalent targeting six
serotypes of Borrelia.15

Cholera vaccine pipeline (Vaccine type: inactivated bacteria)
There is one vaccine candidate in human trials for protection
against Vibrio cholerae infection. This Phase III vaccine is aninactivated bacteria expressing approximately 50% each of
Ogawa and Inaba O1 LPS antigens.
Bacterial – Urinary vaccine pipeline (Vaccine type:
inactivated bacteria)
A combination product for urinary bacterial infection is being
developed outside the U.S. and has completed Phase III trials.

BIO Industry Analysis

13

Vaccine Clinical Pipeline for DNA Virus Pathogens
There are 34 novel vaccine programs for the prevention of
diseases from DNA viruses. As shown in Figure 7, 14 of these
are in Phase I, 14 are in Phase II, and six in Phase III. Currently,
there are no licensing applications under review. Of the seven
DNA virus pathogen indications listed in Figure 7, only two(HPV and CMV) have Phase III programs. More than half of all
programs are for HPV and Varicella (chickenpox), for which there
is prior approval precedent.

More than half of the vaccines for DNA viruses are protein-based
vaccines. All DNA viral pathogen indications listed in Figure 7,
apart from EBV, have at least one protein program. HPV hasfour VLP protein programs in clinical development, whereas
the other protein programs utilize purified protein alone.

COMPANY-SPONSORED GLOBAL CLINICAL PIPELINE FOR DNA VIRUS VACCINES

4

5

0

12

Varicella-Zoster (Chickenpox)

5

3

0

0

8

Hepatitis B (HBV)

1

4

0

0

5

Cytomegalovirus (CMV)

0

3

1

0

4

Herpes Simplex Virus (HSV)

2

0

0

0

2

Herpes-Zoster (Shingles)

2

0

0

0

2

Epstein-Barr Virus (EBV)

1

0

0

0

1

Total

14

14

6

0

34

DNA virus vaccines

Total

3

DNA

Human PapillomavirusrViral(non-replicating)

Total

Viral (attenuated)

BLA

mRNA

Phase III

peptidePhase IIprotein VLP

Phase I

ProteinDNA virus vaccines

Human Papillomavirus

6

4

0

0

0

1

1

12

Varicella-Zoster (Chickenpox)

5

0

0

2

1

0

0

8

Hepatitis B (HBV)

1

0

1

0

0

3

0

5

Cytomegalovirus (CMV)

1

0

0

1

0

2

0

4

Herpes Simplex Virus (HSV)

1

0

0

1

0

0

0

2

Herpes-Zoster (Shingles)

1

0

0

0

0

1

0

2

Epstein-Barr Virus (EBV)

0

0

0

1

0

0

0

1

Total

15

4

1

5

1

7

1

34

Figure 7. The company-sponsored global clinical pipeline for novel DNA virus vaccines. Top: pathogen targets and phaseof program. Bottom: pathogen targets and modality of vaccine.

14

BIO Industry Analysis

HPV (Human Papillomavirus) vaccine pipeline (Vaccine type:protein; protein-VLP; DNA; non-replicating viral vector)
There are 12 HPV vaccines in clinical development, five of which
are in Phase III studies. All but two are protein-based.
The five HPV vaccines in Phase III are protein-based: Onetrivalent, three 9-valent, and one 11-valent. One of the 9-valentvaccines uses VLP for antigen display.
In Phase II for HPV there are two protein vaccines and two
non-protein vaccines. The protein vaccines are 14-valent and9-valent. One of the non-protein vaccines uses electroporated
DNA to deliver E6 and E7 antigen genes (covering HPV types
16 and 18). The second non-protein vaccine in Phase II is arecombinant viral vector vaccine. It uses a two dose, two vector
approach: ChAdOx vector and a second dose using MVA, bothengineered with HPV antigen.
Phase I vaccines for HPV are all protein-based. Two are proteinVLP based vaccines in Phase I that use H. polymorpha, amethylotrophic yeast species to produce the antigens, unlike
the approved protein antigen in Gardasil® which is made using
Saccharomyces cerevisiae. Other differences are the numberof HPV strains added to the vaccine (in this case Type 16 and18, and Type 6 and 11 for the other). Lastly, there is a Phase I
quadrivalent HPV vaccine.
Varicella (Chickenpox) vaccine pipeline (Vaccine type: protein;live attenuated virus, mRNA)
There are eight next generation chickenpox vaccines in thepipeline, all in early-stage human trials. Seven of these (twomRNA, five protein-based) are differentiated from the current
marketed chickenpox vaccines which are live attenuatedvaccines. There is one new live attenuated vaccine candidate
with a new strain of Varicella Zoster.
Hepatitis B vaccine pipeline (Vaccine type: protein; peptide;
non-replicating viral vector)
The next-generation Hepatitis B vaccine pipeline includes threeviral vector and two protein vaccines. A Phase I viral vector
program contains lenti-HBV viral vector with HBV surface
antigen (sAg). A prime boost hybrid vaccine is in Phase II withthe following components: 1) ChAd155 vector with aAg,
modified polymerase and core antigens, 2) MVA vector withsimilar antigens. The second viral vector vaccine in Phase II isa triple component vaccine with the following components:
1) ChAd155-hIi-HBV vector with truncated HBV core antigen(cAg) and full-length small HBV surface antigen (S-sAg), 2) MVA
vector encoding cAg and S-sAg, and 3) the cAg and S-sAg
proteins themselves with AS01B-4 adjuvant.16

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The next-generation protein vaccine in Phase II is a fusion of
HBV PreS L-sAg and peptides derived from the grass pollen
allergen, Phlp5. And lastly, there is a Phase II peptide vaccinethat consists of nine peptides from highly conserved regionsof three different HBV antigens (pol, core, and s) common to
the majority of genotypes.
Cytomegalovirus (CMV) vaccine pipeline (Vaccine type:protein; non-replicating viral vector)
Four CMV vaccine candidates are in clinical development. Twoof these are recombinant viral vector platforms (both in Phase
II), one mRNA (Phase III), and one protein (Phase I/II). The mostadvanced candidate is the mRNA vaccine containing mRNAfor six CMV proteins (gH, gL, UL128, UL130, UL131A, and gB).
One Phase II viral vector program uses two replication-deficientlymphocytic choriomeningitis virus vectors, one expressing
CMV pp65 and one expressing a truncated CMV gB protein.
The other Phase II viral vector program uses modified vaccinia
Ankara (MVA) to express three CMV antigens (pp65,
UL122, and UL123).
Herpes Simplex Virus (HSV-2) vaccine pipeline (Vaccine
type: protein; mRNA)
There are two Phase I programs for HSV-2 infection and genital
herpes. One is an mRNA vaccine with three HSV-2 glycoprotein
mRNAs, and the other is a protein vaccine.
Herpes Zoster (Shingles) vaccine pipeline (Vaccine type:protein; non-replicating viral vector)
There are two Phase I next-generation vaccines for Herpes
Zoster (Shingles). One is a protein vaccine containing VZV
glycoprotein E (gE), and the other is recombinant
vector ChAdOx1 gE.
Epstein-Barr virus (EBV) vaccine pipeline(Vaccine type: mRNA)A single Phase I program exists for Epstein-Barr virus (EBV).
It contains five mRNAs that encode EBV membrane-boundproteins (gp350, gB, gp42, gH and gL).

15

Vaccine Clinical Pipeline for Parasitic Pathogens
There are two pathogens being targeted in the clinic pipeline
for parasites: malaria and schistosomiasis. All of the eight novel
candidate vaccines are in early-stage development (Figure 8).
There is a wide range of modalities being pursued including
protein, protein-VLP, peptide, mRNA, and whole parasite.

Three of the six Malaria vaccines are protein or peptide based.
The two protein-VLP vaccines use Pf circumsporozoite surface
protein (CSP), with one expressing it as a fusion with hepatitis
B sAg (from the yeast Hansenula polymorpha) and the otherusing alphavirus proteins to create the VLP for CSP display. The
third protein-based vaccine uses the same fusion construct
but uses a purified protein (from E. coli). The peptide vaccine
is composed of four salivary peptides isolated from Anopheles
gambiae salivary glands.

Malaria vaccine pipeline (Vaccine type: protein, protein-VLP,
peptide, mRNA, attenuated and whole parasite)
The Malaria vaccine clinical pipeline contains six companysponsored products, three in Phase I and three in Phase II.17

An mRNA vaccine encoding Plasmodium falciparum
circumsporozoite protein is in Phase I.

Two of six Malaria vaccines use live Plasmodium falciparum
parasites in the vaccine. One uses non-attenuated PfSPZ,
allowing the parasites to multiply briefly and co-administratingwith antimalarial drug to kill the parasite, and the other uses
an attenuated strain of PfSPZ.

Schistosomiasis vaccine pipeline (Vaccine type: protein)
There are two protein-based clinical programs for
schistosomiasis, one in Phase I and one in Phase II. The
recombinantly-produced p80 protein is in Phase I. A TSP-2
protein expressed using Pichia yeast is in Phase II.

COMPANY-SPONSORED GLOBAL CLINICAL PIPELINE FOR PARASITIC VACCINES
Phase III

BLA

Malaria

3

3

0

0

6

Schistosomiasis

1

1

0

0

2

Total

4

4

0

0

8

Total

2

1

1

2

6

2

0

0

0

0

2

Total

2

2

1

1

2

8

Total

0

Schistosomiasis

cell

MalariamRNA

Parasitic vaccines

ProteinpeptidePhase IIprotein
VLP

Phase I

Parasitic vaccines

Figure 8. The company-sponsored global clinical pipeline for novel parasitic vaccines.
Top: pathogen targets and phase of program. Bottom: pathogen target and modality of vaccine.

16

BIO Industry Analysis

Vaccine Clinical Pipeline for Novel Combinations
There are ten novel combination vaccines in the clinicalpipeline. All programs are early-stage, and the majority are
mRNA-based as shown in Figure 9. These novel combination
vaccines target seven pathogens (five viral pathogens: SARSCoV2, influenza, RSV (Respiratory Syncytial Virus), MPV(Metapneumovirus), PIV3 (Parainfluenza Virus Type 3),
enterovirus, and coxsackievirus and two bacterial pathogens:
Shigella and E. coli).
Combination vaccines for SARS-CoV-2 + Influenza(Vaccine types: protein; mRNA)
A protein vaccine combining spike from SARS-CoV-2 and HAfrom influenza in a VLP structure is in Phase II. There are also
two vaccines combining mRNA of similar antigens (spike and
HA), one in Phase II and the other Phase I.
Combination vaccine for RSV + Influenza(Vaccine type: mRNA)
There is one Phase I program with a combination mRNA
vaccine for RSV (mRNA coding for prefusion F protein) andthe influenza (mRNA coding for HA).
Combination vaccine for RSV + Influenza + SARS-CoV-2(Vaccine type: mRNA)In April 2023, a Phase I trial completed enrollment for a triple
pathogen mRNA vaccine (RSV + Influenza + SARS-CoV-2).18

BIO Industry Analysis

Combination vaccine for RSV + MPV (Vaccine
types: protein; mRNA)
There are two combination vaccines for RSV and MPV(metapneumovirus), one protein-based and the other mRNAbased. Both are in Phase I and utilize the F surface
protein as antigen.
Combination vaccine for MPV + PIV3 (Vaccine types: mRNA)
There is a Phase I program with an investigational MPV(Metapneumovirus) and PIV3 (Parainfluenza Virus Type 3)mRNA vaccine. The mRNA codes for the F surface protein
for each of the two viruses.
Combination vaccine for Shigella + E. coli (Vaccine types:
attenuated bacteria)
A live attenuated combination vaccine is in Phase I for Shigellaand enteric E. coli. The vaccine is an engineered Shigellabacteria with deletions of surface O-antigen components of
LPS (exposing more conserved epitopes and thus serotypeindependent), and additions of ETEC antigen genes(expressing LTB and a mutated ST).
Combination vaccine for EV71 + CVA16 (Vaccine type:
inactivated viral)
A combination vaccine for enterovirus 71 (EV71) andcoxsackievirus A16 (CVA16) is in Phase I.

17

COMPANY-SPONSORED GLOBAL CLINICAL PIPELINE FORNOVEL COMBINATION VACCINES
Muliple Pathogens

Phase I

Phase II

Phase III

BLA

Total

2

COMBO: COVID + Flu + RSV

1

0

0

0

1

COMBO: RSV + Flu

1

0

0

0

1

COMBO: MPV + PIV3

1

0

0

0

1

COMBO: EV + CV

1

0

0

0

1

COMBO: Shigella + E. coli

1

0

0

0

1

Total

8

2

0

0

10

Total

3

0

bacteria(recombinant)

0

0

Viral
(inactivated)

0

0

mRNA

2

2

proteinVLP

1COMBO: RSV + MPV

ProteinCOMBO: COVID + Flu

1

0

2

0

0

3

0

1

1

0

0

2

0

0

1

0

0

1

COMBO: RSV + Flu

0

0

1

0

0

1

COMBO: MPV + PIV3

0

0

1

0

0

1

COMBO: EV + CV

0

0

0

1

0

1

COMBO: Shigella + E. coli

0

0

0

0

1

1

Total

1

1

6

1

1

10

Muliple Pathogens
COMBO: COVID + Flu
COMBO: RSV + MPVCOMBO: COVID + Flu + RSVFigure 9. The company-sponsored global clinical pipeline for novel combination vaccines.
Top: pathogen targets and phase of program. Bottom: pathogen targets and modality of vaccine.

18

BIO Industry Analysis

Clinical Development Success Rates for Vaccines
As shown in Figure 10, infectious disease vaccines have an Although vaccine success rates for BLA filings for approval are
above average success rate when compared to novel biologics higher than non-vaccines, the number of filings is much lower
and novel small molecule drugs. The success rate for all novel (38 for vaccines vs. 341 for biologics and 466 for small
drugs, across all diseases, is 6.5% for the period 2013-2022. For molecule drugs)
novel biologics (ex-vaccines) the likelihood of approval (LOA)
from phase I is 7.9%. For novel small molecules, the LOA is only
5.6%. The higher 11.0% LOA for vaccines can be attributed tohigher success rates in Phase II and Phase III as well as more
ID Vaccines Non-vaccinmall Molecules
successful BLA filings.
Phase I

Phase II
Phase III
BLA/NDA

51%
48%
30%
26%
29
14
43
54%
50%
67%
37CLINICAL
1
38
94% SUCCESS
88%
97%
DEVELOPMENTRATES FOR VACCINES
5.6%
6.5%
11.0%
7.9%
66

70

136

49%

37

70

107

35%

324

Vaccines (ID only)

Phase Success Rates

Non-Vaccine Biologics
Small Molecules

88%

67%

11.0%
54%

49% 51% 48%
35%

Phase I

97% 94%30%

50%

LOA from Phase I
7.9%
5.6%

26%

Phase II

Phase III

BLA/NDAID Vaccines Non-vaccine
Biologics

Small
Molecules

Figure 10. Clinical success rates for vaccine drug programs for infectious disease. Left: Phase success rates for the period
2013-2022. Right: Likelihood of Approval from Phase I to Approval, vaccines vs. all NMEs across all disease areas. Total
NME/BLA transitions for 2013-2022: N=324 for vaccine, N=4,633 for biologics, and N=6,048 for small molecules. Data
was collected from Citeline’s Pharmapremia database.

BIO Industry Analysis

19

Investment Trends for Vaccine Companies
Venture capital investment into companies with leadproducts of infectious disease vaccines from 2013 to 2022
totaled $2.2 billion in the U.S. and $6.5 billion worldwide.19
This represents 3.4% of total worldwide venture capital raisedfor biopharmaceutical companies during the same period.
By contrast, oncology drug development companies raised$72.6 billion worldwide over the last decade, 12-fold morethan investment in vaccines. The peak year for both typesof companies was during the COVID-19 pandemic in 2021,
with oncology companies raising $17.9 billion and vaccine
companies raising $2.4 billion (Figure 11). Between 2020 and
2022 there were fourteen transactions for vaccine companies
that exceeded $100 million totaling $3.2 billion compared to
two transactions between 2013-2019 equaling $0.6 billion.
This large increase of mega-transactions is likely motivatedby the COVID-19 pandemic. The top five largest transactions,which range from $200 to $700 million and totaling $2.3
billion, are all associated with companies that developed
COVID-19 vaccines.

Between 2013 and 2022, an average of 16 companies withlead products of infectious disease vaccines were financed
each year. By comparison, during the same period there wasan average of 207 oncology companies financed each year.
Breaking the decade into 5-year increments, 63 vaccine
companies received investments between 2013-2018 versus
83 between 2019-2022. In 2022, the largest number ofcompanies was financed at 22, closely followed by 2021 with
21. In 2018, there were only eight venture transactions.
Vaccine-focused emerging companies raised a total of $8.7
billion over the last decade through public share offerings(IPOs and follow-on offerings).20 This compares to $90.7
billion for oncology-focused companies.21 Roughly 70% of
all public emerging company funding for vaccine companies
over the past decade came during the COVID-19 pandemic(2020-2022) ($6 billion of $8.7 billion).

GLOBAL VENTURE INVESTMENT INTO COMPANIES 2013-2022
WITH LEAD VACCINE PROGRAMS

Oncology$9.8
Oncology
Oncology

Total Raised ($B)

$16
$8

$7.4

$12
$6
$3.7

$4$8
$3$6
$2$4 $1.5$1$2 $1.5
$0$0

$2.0

Total Raised ($B)

$3.1

$4.4

$7
$14
$6
$12
$5
$10
$4$8
$3$6

$2.3

$2$4
$1$2
$0$0

2013 20142014 2015
2015 20162016 20172017 20182018 20192019 2020
2020 2021
2021 2022
2022
2013

$0.1
$0.2
$0.1 $0.1$0.1 $0.2

$0.6
$0.5
$0.5 $0.2$0.3$0.2 $0.6 $0.3

$1.4
$1.4

$2.3

$0.7
$0.7

2013
2013 20142014 2015
2015 20162016 20172017 20182018 20192019 2020
2020 2021
2021 2022
2022

Figure 11. Left: Venture funding of companies with lead products in oncology, 2013-2022. Right: Venture funding of100%$20
companies with lead products in ID vaccines, 2013-2022.
Infectious Disease Vaccines

$16
$14

$3.1

$8.7

Percent of BioPharma VC

90%

$18

80%

$16

70%

$14

Total Raised ($B)

$18

$3.7

$7.4

$9.8

% of Total VC in USA

$20

$2.0

$4.4

Infectious
Infectious Disease
DiseaseVaccines
Vaccines

$8
$16

$14.0

$14
$7
$10
$5

$9
$18

Total Raised ($B)

$18
$9

$10
$20

$17.9

$8.7

$12

60%

$10

50%

$8

40%

$6

30%

$4

20%

$4

$2

10%

$2

$0

0%

$0

Cancer

80%
70%

$12
$10
$8

20

29%
$1.5

30%
$2.0

36%
$3.7

90%

$14.0

Percent of BioPharma VC

$6

100%

$17.9

32%
$3.1

38%
$4.4

$7.4
40%

$8.7
47%

$9.8
45%

60%
50%
40%

39%
30%

30%
20%
10%

0%

0%

BIO Industry Analysis% of Total VC in USA

$20
$10

Part 2. Prophylactic Antibodies
History of Prophylactic Antibodies
Blood serum with anti-toxoid antibodies for tetanus anddiphtheria was first used to combat infectious disease in the
1890s. These early blood-derived antibodies were from infectedhorses, not of high purity, and had protective efficacy for only
a few weeks. Contamination and unforeseen side effects inearly use of these antibodies eventually led to vaccines being
the preferred prophylactic intervention for tetanus anddiphtheria. For other infectious diseases there was substantial

progress in the development of serum-derived antibodies in
the 1890s and by the late 1900s the first monoclonal antibodies
were approved for prophylaxis. Today, there are prophylactic
serum-derived antibodies available for use in rabies and CMV
and monoclonal therapies for RSV, anthrax, and COVID-19.
Appendix II provides a more detailed description of all
previously approved prophylactic antibodies.

TIMELINE OF APPROVED PROPHYLACTIC ANTIBODIES
Decade of 1st
License or Usage

#

1890s

1

RabiesRabies lyssavirus

RNA virus

2

CMV disease

Cytomegalovirus

DNA virus

3

RSV

Respiratory syncytial virus

RNA virus

4C. diff infection

Clostridioides difficile

bacteria

5

AIDS

Human immunodeficency virus

DNA virus

6

Anthrax

Bacillus anthracis

bacteria

7

Covid-19

SARS-Cov2

RNA virus

1990s

2010s

2020s

DiseasePathogen Name

Pathogen Type

Figure 12. History of prophylactic antibodies listed by date introduced and pathogen name and type.

BIO Industry Analysis

21

Clinical Pipeline for Prophylactic Antibodies
There are 17 antibodies in clinical development that havedisclosed development programs for prophylactic use against
infectious diseases. The majority of the programs (76%) target
RNA viruses, and no programs cover DNA viruses nor
parasitic infections.

Prophylactic Antibodies for SARS-CoV-2
There are more than 60 antibodies in clinical development for
COVID-19, many of which are for pan-coronavirus infection or
new variants. However, most of these are antiviral treatments,
not prophylactic therapies. We identified four clinical-stage
antibodies in development with the stated goal of prophylaxis.

HIV
There are two mAbs for HIV in Phase II. One is a tri-specificantibody specifically for the T-cell CD4 site of envelope
glycoprotein gp120, the V1/V2 region of gp120, and gp41. The
second Phase II program is testing an anti-gp120 mAb thatbinds the V3 glycan region specifically and is being tested in
combination with other mAbs.

cocktail were derived from a patient during the 2013-2016 Ebola
outbreak in Africa.

Community-acquired bacterial pneumonia (CAP)
There is a bacterial biofilm disrupting monoclonal antibody inPhase I for community-acquired bacterial pneumonia. A wide
range of bacteria can cause CAP, such as Streptococcus
pneumoniae, Haemophilus influenzae, Moraxella catarrhalis,
Staphylococcus aureus, Group A Streptococci, Legionella,
Mycoplasma, Chlamydia pneumoniae, and C. psittaci.

Chikungunya
There is one fully human mAb in Phase I for chikungunya
infection. It is derived from a patient infected with thechikungunya virus.

Zika
The Phase I antibody product for Zika is a purified gamma IgG
fraction of human plasma containing polyclonal antibodies
reactive to Zika.

Influenza

Marburg

There is a single quadrivalent pandemic and seasonal influenza
antibody in Phase II. It is a fully human polyclonal antibody
against four strains of the influenza virus including both type
A and B infections.

A human antibody derived from a survivor of Marburg is in
P h a s e I . T h i s i s a p ote nt i a l p a n - M a r b u rg v i r u s
prophylactic remedy.

Staphylococcus
There are two mAbs for Staphylococcus, one in Phase II and
one in Phase III. The Phase III mAb is a human IgG1 that binds
S. aureus alpha-toxin. The Phase II mAb targets bacterial surface
polysaccharide, poly-N-acetylglucosamine.

RSV
There is one Phase III RSV antibody in the pipeline. As with therecently approved Beyfortus™ (nirsevimab), this candidate
antibody also binds to the pre-fusion conformation of F protein.

Tetanus
There is one Phase II antibody for tetanus that binds thetetanus toxoid.

Ebola
Although treatment antibodies have been approved, noprophylactic antibodies have been approved. Two postexposure antibodies were FDA approved in 2020: Ansuvimab(Ebanga ™) and the triple antibody cocktail of atoltivimab,
maftivimab and odesivimab (Inmazeb™). These antibodies
target the EBOV trimeric glycoprotein. There is one double
antibody cocktail in development. Both antibodies in the22

BIO Industry Analysis

COMPANY-SPONSORED GLOBAL PROPHYLACTIC
ANTIBODY CLINICAL PIPELINE
Pathogen Type

Phase I

Phase II

Phase III

BLA

Total

RNA virus

6

3

3

0

12

Bacteria

1

2

1

0

4

DNA viruses

0

0

0

0

0

Parasites

0

0

0

0

0

Total

7

5

4

0

16

Phase I

Phase II

Phase III

BLA

Total

Pathogen
SARS-CoV-2

1

1

2

0

4

HIV

2

0

0

0

2

Influenza - Seasonal

0

1

0

0

1

Staphylococcus

0

1

1

0

2

RSV

0

0

1

0

1

Tetanus

0

1

0

0

1

Rabies

0

1

0

0

1

CAP

1

0

0

0

1

Chikungunya

1

0

0

0

1

Zika

1

0

0

0

1

Marburg

1

0

0

0

1

Total

7

5

4

0

16

Figure 13. The company-sponsored global prophylactic antibody pipeline. Top: pathogen type and phaseof program. Bottom: pathogen target and phase.

BIO Industry Analysis

23

Discussion
Vaccine R&D Pipeline in the Context of Vaccine Markets
The clinical pipeline for infectious disease vaccines across theglobal biopharma industry consists of 249 company-sponsorednovel clinical-stage programs. On the surface, this sounds likea significant number of vaccines; however, “infectious disease”
is not a single threat, rather it comprises many highly
differentiated threats. Unlike oncology, where one drug mightwork on multiple cancer types, one vaccine will likely only work
for a single pathogen. Further, 28% of the total programs (n=69)
are for vaccines against SARS-CoV-2. The remaining vaccine
programs are spread across 46 different pathogens, many with
only one vaccine in clinical development (e.g., Epstein-Barr virus,
West Nile virus, chlamydia, gonorrhea, and Lyme disease) andthere are many infections without a single vaccine program at
the clinical development stage. Resistant bacterial pathogens,for example, are not well represented in the pipeline with only
two of the six ESKAPE pathogens having ongoing
vaccine programs.22
With the likelihood of FDA approval from Phase I calculated
at 11%, this means that to statistically ensure approval of a
vaccine for each pathogen, 10 programs must enter clinicaldevelopment. For many infectious diseases, particularly low
incidence and tropical diseases that disproportionately
affect low- and middle-income countries, there are far fewer
than 10 developmental vaccine programs initiated in recent
years, signaling that more investment and innovation isneeded. Currently, only 10% of the infectious disease threats
pursued in the vaccine pipeline have 10 or more ongoingprograms, and only 20% have five or more. The lack ofbreadth may, at least partially, be due to the unique market
issues surrounding vaccines.
In comparison to antibiotics, vaccines face a very different typeof marketplace. For many vaccine categories there is a relatively
clear set of possible populations that would be appropriate for
immunization. These populations might be very targeted –occupational risk, travel, specific underlying health risks or
conditions – while others may be broader groups, such as all
infants or all adults over age 65. However, other vaccines faceunique market challenges. For example, vaccines targeting
pandemic pathogens face an uncertain future market. For
investors and developers, this uncertainty limits the number ofvaccines in development that could be leveraged for
pandemic preparedness.
Prior to reaching the market, vaccines also endure a hurdle thatis not present for antibiotics and other drugs – government
advisory recommendations for use. For vaccines, approval by
the regulatory authorities is only the first step to their utilization.
Once approved, vaccines are evaluated for specificrecommendations by National Immunization Technical Advisory
Groups (NITAGs) that define where each vaccine will have themost public health, societal and individual benefit. For example,
in the U.S., the CDC’s Advisory Committee on Immunization
Practices (ACIP) conducts these evaluations, advises the Directorof the CDC on vaccine recommendations, and creates thenation’s immunization schedules. This process is vital to defining
the actual market for a vaccine and, in many countries, guides
clinician decision-making, leads to mandatory coverage in bothpublic and private insurance programs, and ultimately drives
access for patients. Because of this important two-step process(approval and recommendation), innovation in vaccines is partly
driven by vaccine developers’ and investors’ confidence andunderstanding of how a novel vaccine might be recommended
by these Advisors.
Once these recommendations are in place other key areas also
contribute to market adoption. National infrastructure thatprovides and facilitates access to vaccines across many different
types of providers, rapid coverage implementation by insurance
programs, and clear messages that build vaccine confidence
among the public all impact the market for vaccines.
Historically, investment into infectious disease vaccine
companies has been a small percent of the total emerging
biopharmaceutical funding. For example, only 3.4% of total
venture capital raised for biopharmaceutical companies during
the last 10 years went to companies with infectious diseasevaccine programs. That includes the peak funding years during
the COVID-19 pandemic. By contrast, oncology drug
development companies receive 38% of venture capital and
12-fold more dollars than vaccine companies.
Although more investment is needed to cover future andemerging pandemic threats, as well as regional and tropicalinfections, much has been achieved through innovations invaccine science. The recent approvals of the first RSV vaccines
are just one example. COVID-19 gave us a new benchmark for
how vaccines can be developed using new moleculartechnology, quickly translated into clinical studies and movethrough the development, approval and manufacturing
processes. In the last few years, achievements have also been
made with Ebola and malaria vaccines. Given recent approvals,
there are currently vaccines approved for 34 unique pathogens.
Furthermore, recent licensed vaccines utilize a wide range ofmodalities: direct antigen delivery (e.g., protein, carbohydrate,
pathogen inactivation and pathogen attenuation) and indirect
antigen delivery (e.g., mRNA and viral vector-based vaccines).
There are now 53 RNA-based and 11 DNA-based vaccines in
the clinic, 27 recombinant viral vector-based vaccines and 65%of the protein-based vaccines now use virus-like particles (VLPs)
that more efficiently display epitopes to immune cells.
Furthermore, innovation in the vaccine space over the last
decade has had above average clinical success rate for approval
from Phase I, 11% for vaccines compared to only 5.6% for novel
small molecules.

24

BIO Industry Analysis

There is also progress being made with prophylactic antibodies.
Although the clinical pipeline for prophylactic antibodies issmall relative to vaccines, with only 16 in clinical-stage
development, the antibody pipeline targets 11 different
pathogens. With historic precedent and recent successes, suchas the RSV monoclonal antibody approval this year, the sector
could grow beyond the current seven prophylactic antibody
approvals for viral and bacterial pathogens.23
Development of vaccines is often cited as one of the greatest
public health successes of the 20th century. Infectious diseases,
such as smallpox and measles, were once great causes ofmorbidity and mortality worldwide. As an example, decadesof broad immunization against measles led to a 99% reduction
in related complications like encephalitis and death whencompared to the pre-vaccine era. 24 We now have acomprehensive routine childhood vaccine schedule as well asa schedule for adult immunizations in the U.S. that provide
protection against 20 pathogens. Most of the current vaccines
on the market prevent infectious diseases with well-establishedincidences of disease in children, adolescents and adults. This
makes their potential market and utilization more predictablefor vaccine developers and their investors. Vaccinations acrosspeople’s life span offers many direct and indirect benefits toindividuals, communities, society and the economy. Childhood
immunization has had the largest impact to date. A CDC
analysis of childhood vaccination showed that U.S. children
born between 1994 and 2018 who were fully vaccinated would
benefit from the prevention of 419 million illnesses, 26.8 million
hospitalizations and 936,000 deaths. These reductions save an
estimated $406 billion in direct healthcare costs and nearly $1.9
trillion in total societal costs. The high levels of vaccination inchildren demonstrated benefits for the overall U.S. population,
preventing more than 24 million illnesses spanning all ages
and decreasing hospitalizations related to multiple different
infectious diseases.

Solutions to Strengthen Innovation
BIO posits there are four main policy areas that can help
stimulate innovation, increase investment, and close gaps inremaining unmet medical need for vaccines which, if
unresolved will result in continued underfunded levels ofinvestment in vaccine development. With the policy areas
discussed below, we believe there is a way to make vaccines
a more predictable venture, spurring innovation and investment
and curing or protecting the world from diseases that debilitate(acutely or chronically) or shorten life spans.

world. As we look across the vaccine pipeline, we must
understand the impact an ACIP (and other global NITAGs)
recommendation will have in defining the potential market
size and patient utilization for every vaccine currently indevelopment. Clarifying what data can lead to the mostimpactful recommendation for each type of vaccinepreventable disease will increase the predictability andconfidence in terms of product characteristics and forecasted
market size. Many novel vaccines will focus on providing
protection to eligible subpopulations at risk, for example
prevention of pre-operative bacterial infections in persons at
risk of recurrent antimicrobial infections. These vaccines aredesigned to reduce the infectious disease burden in a target
group rather than the entire population.
ACIP proved during the pandemic that it could appropriately
evaluate data in a timely fashion to ensure access, as well ass
communicate to clinicians critical data. While the urgency of apandemic is now in the rear view mirror, there are best practices
from the pandemic that should be maintained. Indeed, the
CDC has taken steps to formalize some of those processes For
example, the CDC now stipulates that ACIP recommendations
are considered final upon CDC Director adoption. This is a
critical signal to payers that coverage of these products is
effective. At the same time, the CDC is taking steps to post
clinical guidelines faster, through new ACIP updates, rather
than waiting for publication in the MMWR. This is also a
promising development in ensuring that novel products reachpatients faster. However, it is critical that this new process issustained for all products.
Creating an environment where novel vaccine candidates canbe reviewed and recommended is a vital part of stimulating
innovative vaccine development. To do this, the ACIP process
must adapt to the changing development landscape. The CDC
can help create an environment that encourages innovation
by implementing some new approaches to the review process.
•

The CDC should add more expertise in subpopulations such as geriatrics and complex chronic
diseases to the voting committee. The addition ofsuch experts will provide important medical
perspective on how infectious diseases affect key
individuals and populations of interest.

•

CDC staff should increase their understanding of thevaccine pipeline and the new technologies being
deployed by industry. Deepening CDC’s awareness ofthe vaccine pipeline will allow them to better plan
reviews, resource review committees appropriately
and provide valuable guidance to industry related tothe types of data needed for clear recommendations.

1. Evolve ACIP Processes
The first policy area that will have a vital effect on vaccine
innovation is the NITAG recommendation process. In particular,
the CDC’s ACIP evaluation and recommendations
fundamentally shape one of the largest vaccine markets in the

BIO Industry Analysis

25•

CDC should create an infrastructure within the ACIP
process that evaluates issues important for theevaluation of all vaccines. These topics might include
guidelines on best approaches for health economics
analysis, especially for more niche vaccines, or sharedevaluations of vaccines using platform technologies,
or guidance for working groups and industry on thedata required for preferential recommendations.

Changes such as these will provide more clarity for vaccine
developers on the ACIP processes thereby providing clear
recommendations for new vaccines. Vaccine developers andtheir investors would then be more likely to pursue vaccines
for more narrow populations or unique infectious diseases.
In addition, refinment of this process may serve as indicatorfor other NITAGs around the world. Adding more predictability
to the recommendation process for new categories of vaccines
can increase the likelihood of successful access, uptake anduse in many countries.
BIO has been working with leaders and stakeholders tocontinue to strengthen the ACIP recommendation process andto consider what factors for recommendations will be
important for evaluation as the vaccine pipeline becomes morediverse and impacts more sub-populations.
2. Access to Vaccines
Continued increases in vaccination across the life span could
prevent even more illness, hospitalization and death whilesaving healthcare expenditures.
Of course, the reductions in disease and the economic benefits
can only be maximized if immunization rates are high forchildren, adolescents, pregnant people, adults and seniors.
One of the most important policy areas relates to increasing
access to vaccines across the life span of every person. Overthe last few years significant gains have been made related toaccess to vaccines for adults. The Affordable Care Act (ACA) of
2010 contained provisions that require ACIP-recommended
vaccines be made available in most private insurance plans
and Medicaid expansion populations with no cost-sharing ($0out-of-pocket patient cost). Passage of the Protecting Seniors
Through Immunization Act and the Helping Adults Protect
Immunity (HAPI) Act, both passed as part of the Inflation
Reduction Act of 2022, helped provide this same important
benefit for seniors with Medicare Part D plans and Medicaid
adults not covered through the ACA. These legislative changes
mean that approximately 9 of every 10 Americans now haveaccess to vaccines in private and public insurance programswith no out-of-pocket costs for the individual. But work stillneeds to be done on the access front so that all Americans,especially uninsured adults between 19 and 64 years old, canaccess vaccines with no out-of-pocket cost. Given the broad
benefits of primary prevention to individuals and society,especially for persons with underlying chronic conditions,facilitating access to immunizations through both financial
policies and policies that increase the types of vaccinators (forexample pharmacists) will have a significant impact on overall
healthcare outcomes and costs. So, while progress on financial
and access pressures are improving there is still more work to
be done to remove all barriers to equitable access to thesepreventative interventions.
BIO continues to work closely with stakeholders to put forward
both legislative and regulatory solutions that will reduce bothfinancial and physical barriers to immunizations for everyone.

26

BIO Industry Analysis

One important policy area focuses on policy solutions that
increase the reimbursement for vaccine providers across public
and private insurance programs. Some solutions focus on
broadening the types of medical professionals that canadminister vaccines, from nurse practitioners to pharmacists.
Lastly, BIO is evaluating policy solutions that increase funding
and authorities that allow state and federal programs topurchase vaccines for uninsured adults. The goal is to ensure
those who desire vaccines can receive them with no or very
low out-of-pocket cost at the immunization site best
suited to them.
3. Platform Technologies
The advances made before and especially during the COVID-19
pandemic offer an opportunity to increase investment in newtechnologies that can conquer infectious diseases that havebeen scientifically challenging, like HIV and malaria. These newplatform technologies can speed development of novel
approaches to improve efficacy and/or safety in areas where
there are already vaccines. They also offer important
advantages as we prepare for the next infectious disease
outbreak or pandemic as they could facilitate investment in
R&D across viral families – pan coronaviruses, filoviruses,
orthopox viruses, etc. – so that we can pivot from a vaccine
developed for commercial purposes to quickly develop anduse a vaccine platform for another pathogen in that samefamily. Although records were broken with COVID-19, this may
not be the case in the next pandemic. Early preparation, better
cataloging and understanding of the characterization of viralfamilies, advanced approaches using new biotechnologicalplatforms, and more funding of translational research
will be required.
Recent U.S. legislation created a formal “Platform Technology
Designation” program at the FDA. BIO and its members haveadvocated for broad interpretation and implementation of the
program to be forward thinking and allow for the greatest
impact on the development of vaccines in and outside publichealth emergency situations. BIO has also strongly supported
legislative efforts to fund a pandemic development programthat would leverage platform technologies to do R&D on
vaccines for viral families that include pathogens ofpandemic potential.

acceptance (the willingness to take a vaccine) is crucial.
Improving vaccine confidence requires a coordinated effort ofclear communication, from trusted community and publichealth messengers, describing the benefits and risks to people
that is supported by thorough data collection and analyses. In
recent years, there have been increases in vaccine hesitancy– seen most glaringly through the COVID-19 pandemic – thatthreaten the important advances in disease burden andreduction due to vaccines and future vaccine candidates.
Combatting vaccine misinformation and disinformation andbolstering vaccine confidence is crucial to realizing the broadest
benefits of vaccines and a stronger vaccine infrastructure
overall. Efforts for effective communication on who needs a
vaccine, when, and why they are important, should beprioritized to ensure that the vaccines we currently haveavailable reach individuals, and an environment exists for strong
investment in future vaccine development.
As more vaccines are approved for adult populations, efforts
to strengthen vaccine confidence are of particular importance.
Historically, adults have had lower vaccination rates thanchildren in the U.S., likely due, in part, to inconsistent andunclear messaging and lack of a published adult vaccination
schedule by the CDC. Partnerships between community- basedorganizations, governments, medical leaders, policymakers,
industry and non-governmental groups have proven trackrecords in providing and arming communities with vaccine
knowledge. Empowering individuals and families with
scientifically valid information they can trust is key to ensuring
both individuals/families and governments are making thebest decisions for themselves and their communities. These
partnerships need to proliferate and be coordinated if we want
to see a meaningful increase in the acceptance anduptake of vaccines.
We must enact policies and support community engagement
and educational activities that will help prevent and/or mitigate
the life-altering consequences of pathogens discussed in thepaper and the unknown threats on the horizon. BIO has andcontinues to support community-based organizations in theireducational efforts.

Conclusion

Innovations in vaccine development and successful vaccine
candidates are only worthwhile if the population is willing toreceive vaccines. In 2018, 13.5 million children across the globe
were not vaccinated.25 The COVID-19 pandemic had a negative
impact on routine immunization for children, adolescents andadults worldwide, due to missed or delayed health services,and school and facility closures.. In addition to vaccine access(the ability for individuals to get vaccines if they wish), vaccine

The Biotechnology Innovation Organization (BIO) and member
companies view innovation as the key to combating current
and future threats in infectious disease. Small emerging
biotechnology companies are developing 62% of the vaccinesand prophylactic antibodies described in this report.
Maintaining this trend where from entrepreneurs and earlystage investors are willing to take on substantial risks, will
require continued funding for basic and translational research,a health care system that values solutions to potential threats,
and a policy environment that incentivizes innovation.

BIO Industry Analysis

27

4. Rebuilding Vaccine Confidence Worldwide

Appendix I – Approved Vaccines
Smallpox Vaccines (Pathogen type: DNA Virus. Vaccine type:
live attenuated)

Rabies Vaccines (Pathogen type: RNA Virus. Vaccine type:attenuated, inactivated)

The earliest mass vaccinations for smallpox trace back to theearly 1800s. However, these smallpox vaccines were notpurified, nor derived from a single source. For 130 years,
different crude extracts from blister pus were used around theworld in arm-to-arm transfer.26 These vaccines likely included
cowpox, horsepox, or polyclonal variants of similar viruses.27
The heterogeneity and sourcing of these vaccines, while
efficacious, raised safety concerns in multiple countries. In the
U.S., it was not until 1931 that the FDA licensed a single pooled
strain of “vaccinia” virus for the smallpox vaccine (Dryvax®).
Other countries had different pools of vaccinia virus, somemore pathogenic than others. We now know throughsequencing historic samples that these pooled poxviruses used
for mass vaccination were closer to horsepox than the cowpox
strains used in the original Edward Jenner clinical experiments
dating back to 1796.

Louis Pasteur is credited with developing an “attenuated” rabies
virus in 1885 through the method of serial passaging in rabbits.
For this rabies vaccine, he extracted suspensions of infected
rabbit spinal cord tissue and inactivated them by air drying andlater via chemicals.33 Due to longer onset of the viral disease,post-exposure vaccination was possible for rabies. Improved
versions of the original method, such as modifying theinactivation process, allowed for use in large populations in
the early 1910s.

Production of the vaccines at scale in the early 1900s was
carried out by growing the virus on the skin of calves, whichrisked contamination. By the 1940s, vaccinia virus vaccine could
be grown in eggs for more control over contamination.
However, it was not until 2007, that a single, purified isolate of
the vaccinia virus, ACAM2000™, received an FDA license.28 Thisvaccine is produced in Vero cells, a commonly used cell line
derived from an African green monkey kidney in 1962.29
Other versions of the smallpox vaccine are based on lab
generated mutations of vaccinia strains using serial passaging,
the process of growing a pathogen in cells or whole animal in
iterations. In the 1960s, the Modified Vaccinia Ankara (MVA)
mutant poxvirus was developed by German researchers after
serial passaging Turkish vaccinia strains in chicken embryo cells.
This MVA strain had the advantage of being non-replicating
due to attenuating DNA mutations and was used successfullyin the 1970s vaccination campaign in Germany.30 Around thesame time, a replicating attenuated strain of vaccinia wasdeveloped and manufactured by Kaketsuken in Japan.31 A
further passaged clonal strain of MVA, known as MVA-BN (usedin Jynneos®, Imvanex®, and Imvamune®) was approved inEurope in 2013 and in the U.S. in 2019.32 MVA-BN is nonreplicating and manufactured using chicken embryo cells.
In Figure 2 the smallpox vaccine type is categorized under live
attenuated vaccine type. All of the smallpox vaccine examples
above, whether replicating or non-replicating, lab attenuatedor naturally attenuated (by using a cowpox or horsepox
relatives), fall into the live viral category. The main differences
throughout the history of smallpox vaccination are the purityof the virus, the move from polyclonal to clonal, and the degreeof attenuation.

In the mid-20th century, production techniques moved fromrabbit nerve tissue to chicken eggs, and later to human diploidcells in the 1970s. Various methods of viral inactivation or
production evolved during this time such as the use of
B-propiolactone, adsorption to aluminum phosphate, and theuse of duck embryo cells (Lyssavac N®). By the 1980s,
continuous Vero (African green monkey kidney) cell lines wereused.34 This version is known as the Purified Vero Cell Rabies
Vaccine (PVRV) due to the required DNA removal step fromthe Vero cells. It is used primarily outside the U.S. under trade
names such as Verorab®, Imovax® – Rabies vero®.
Currently licensed vaccines in the U.S. use attenuated,inactivated vaccine types: RabAvert®, grown in primary culturesof chicken fibroblasts, and Imovax®, made using human lungfibroblast diploid cells.35
Cholera Vaccine (Pathogen type: bacteria. Vaccine type: live
attenuated whole cell; [inactivated])
The earliest cholera vaccines for prevention of the diseasecaused by the bacterium Vibrio cholerae date back to the late
1800s. These were inactivated whole cell vaccines used only inlimited populations as they were reactogenic and had limited
efficacy. Broader vaccination only came a century later withthe advent of second-generation vaccines that utilized modern
cloning techniques. Starting in the 1990s, efficacious oralcholera vaccines were licensed. The first was a monovalent,
killed whole-cell bacteria (O1 serogroup) mixed with cholera
toxin B subunits (Dukoral™). The toxin B subunits (called CTB
or rBS) are made recombinantly in a strain of Vibrio choleraethat lacks the gene for subunit A (both subunits are required
to form the toxin).36 The second widely used cholera vaccine
is a bivalent vaccine using the O1 and O139 serogroups, bothwith deleted CTB genes (Shanchol™/Euvichol™). Although thetoxin gene deletion had been used in the Vietnamese mORCVax™ vaccine, the Shanchol™/ Euvichol™ vaccine is preparedin a new way. Two of the original O1 strains (with CTB genedeletions) are grown and killed by heat, which allows
lipopolysaccharides (LPS) to develop at higher levels.
Separately, a O139 strain, one additional O1 strain, and the two

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classical O1 strains are each inactivated using formalin andadded to the final product.37
A live, attenuated cholera vaccine was also developed. Thisvaccine was licensed around the world as Orochol®, and later
as VAXCHORA® in the U.S. This live bacteria vaccine is the firstand only cholera vaccine approved in the U.S. (2016). Unlike
the majority of attenuated viral vaccines, the live attenuatedcholera vaccine was not created by serial passage. The
attenuation was designed using genetic engineering by
deleting the catalytic domain of cholera toxin. Selective
targeting of the deletion allows the non-toxic subunit of CTB
to remain available for immunogenic response.38
Tuberculosis Vaccines (Pathogen type: mycobacteria. Vaccine
type: live attenuated cell)
The attenuated Mycobacterium tuberculosis cell has been used
as an oral tuberculosis (TB) vaccine since the early 1920s.
However, this BCG vaccine (named after Calmette-Guerin who
attenuated the original Bacilli strain) had many twists and turns
in its history before, and even after its administration to morethan 4 billion individuals worldwide.39 Widespread vaccination
outside the U.S. did not occur until the 1950s. Prior to that,
results from clinical studies in different regions showed
conflicting efficacy data. This is in part due to different regions
having various levels of background mycobacteria exposurein their respective environments, thus casting doubt on thecontrol group’s naïve immunity. Furthermore, as seen with earlysmallpox vaccination campaigns, different strains of
Mycobacterium tuberculosis were being used in different
regions of the world (in the 1920s-1960s, there was not amethod technologically capable of differentiating
bacterial strains).
Eventually, single strains of Mycobacterium tuberculosis wereused in the attenuated vaccines. The BCG vaccine licensed in
the U.S. uses the TICE strain developed at the University of
Illinois. Outside the U.S. various strains are used, such as theDanish, Japanese, Bulgarian, and Indian strains, each withvarying immunogenic properties in lab studies.40

the early 1900s, the diphtheria toxoid itself was isolated as atoxin-antitoxin (TAT) mixture and used as a vaccine. Laterversions of the vaccine, some that remain in use today, include
mutated variants of the diphtheria toxin alone. The common
production method involves growing Corynebacterium
diphtheriae in cow extracts, detoxification with formaldehyde,
followed by purification using ammonium sulfate fractionation,
dialysis or column chromatography and finally adsorption onto
aluminum phosphate.43
Today, the diphtheria vaccine is only available in combination
products in the U.S. and most other countries. The
combinations have expanded to include up to six components,
including acellular Pertussis (aP), haemophilus influenza type
B (Hib), hepatitis B (HepB), tetanus (T). For example, it is incombinations such as the bivalent (DT), trivalent (DTaP),
quadrivalent (DTaP + Hib or DTaP+ HepB), pentavalent(DTaP+Polio + Hib or DTaP + Polio+ HepB), or hexavalent (DTaP+ Polio + Hib + HepB) combinations as well as the quadrivalent
adult formulation TdaP. Name brand vaccines in the UnitedStates include Daptacel®, Infanrix®, Kinrix™, Pediarix®, Pentacel®,
Quadracel®, and Vaxelis®.44
Yellow Fever Vaccines (Pathogen type: RNA virus. Vaccine
type: live attenuated)
A live attenuated vaccine against yellow fever (YF) was
deployed for broad use in the 1930s. The original vaccine wasmade via serial passaging in chicken and mouse tissue toattenuate the YF RNA virus. The 17D strain had the added
advantage of not mutating as rapidly as its ancestral strains,
allowing for more homogeneity once replicating in vivo. There
are now three substrains of 17D manufactured in various partsof the world (known as 17DD, 17D-213, and 17D-204.45 The
currently licensed yellow fever vaccine for the U.S. is YF-VAX®,
a 17D-204 strain grown in chicken embryos and purified bycentrifugation.46
Pertussis vaccines (Pathogen type: bacteria. Vaccine type:protein; [inactivated])

Vaccines for Corynebacterium diphtheriae bacterial infection(diphtheria) use the secreted toxin (capable of shutting down
human cell translation) as the antigenic component.41 A
diphtheria anti-toxoid serum was first used to combat thebacterial disease in the 1890s and included a mixture ofantibodies and other blood components derived from infectedhorses. This mixture was inconsistently produced and of low
purity. As a result, contamination and unforeseen side effects
were discovered creating a need for a vaccine alternative.42 In

A vaccine against the bacterium Bordetella pertussis (thecausative pathogen of whooping cough) was developed in
the 1920s-1930s and approved for broad use in the 1940s. The
original vaccine used inactivated whole cell pertussis bacteria(wP) as the inoculant and quickly became part of the
combination vaccine product, DTwP (diphtheria, tetanus, andwhole cell pertussis). Decades later, in the 1990s, acellular formsof the pertussis vaccine were used broadly as companies
discontinued the whole cell formulations. These acellular
pertussis (aP) vaccines are multivalent and combine multiple
proteins of the bacterium Bordetella pertussis, such as the large
pertussis toxin (PT), Filamentous Hemagglutinin (FHA), Pertactin(PRN), and Fimbriae (FIM). The aP vaccine was combined withBIO Industry Analysis

29

Diphtheria Vaccines (Pathogen type: bacteria. Vaccine type:protein subunit)diphtheria and tetanus comprising the DTaP vaccines used
today, such as Adacel® and Boostrix® in the U.S.47
Te t a n u s V a c c i n e s ( P a t h o g e n t y p e : b a c t e r i a .
Vaccine type: protein)
The Clostridium tetani bacteria secretes a toxoid protein that
infiltrates motor neurons causing the disease known as tetanus,
commonly referred to as lockjaw. As was the case with
Corynebacterium diphtheriae described, the original vaccine
was comprised of this toxoid protein itself. It was developedin the 1920s and used broadly in the 1940s. This highly
efficacious version remains the only tetanus vaccine today. It
is produced as a monovalent form, but more commonly in
combination with other vaccines. For example, bivalent (DT),trivalent (DTaP), quadrivalent (DTaP + Hib or DTaP+ HepB),
pentavalent (DTaP+Polio + Hib or DTaP + Polio+ HepB), and evenhexavalent (DTaP + Polio + Hib + HepB).
A common production method for the tetanus toxoid protein
vaccine involves growing Clostridium tetani in cow extracts,
detoxification with formaldehyde, followed by purification
using ammonium sulfate fractionation, dialysis or columnc h r o m a t o g r a p h y a n d fi n a l l y a d s o r p t i o n o n t oaluminum phosphate.48
Polio Vaccines (Pathogen type: RNA virus. Vaccine
type: inactivated)
The first inactivated polio virus (IPV) vaccine was developed
and approved in the 1950s. However, production issues forinactivating the polio virus were discovered in the early launcho f t h e s e p ro d u c t s a n d o t h e r va cc i n e a p p ro a c h e s
were developed.49
In 1961, a live-attenuated oral vaccine for polio (OPV) wasapproved for use.50 The attenuated viral strains were developedin the 1940s via serial passage, first in cell cultures then in rats
and mice.51 Production, like IPV described above, is done withattenuated virus particles purified; however, without theinactivation step. Due to it being a live virus, the vaccine could
be given orally, including on sugar cubes for children. This oral
polio vaccine has not been used in the U.S. since 2000.
In the 1980s, scientists discovered that purification of the polio
virus before inactivation with formaldehyde was more efficient,and the addition of various purification techniques could
enhance potency. An enhanced inactivated polio vaccine (eIPV)
was approved in the U.S. in 1987.52
In the U.S., there is one licensed inactivated trivalent polio
vaccine that is not combined with DTaP: IPOL®, type 1,2,3
polioviruses grown in Vero (African green monkey kidney) cells.
A previously approved inactivated viral vaccine made fromhuman diploid cells (Poliovax®) has been discontinued. The

trivalent approach has been the standard since the 1960s. Other
polio vaccines are in the four combinations with DTaP describedabove, either with or without rHepB or HIB, or both.53 Similar
products are manufactured outside the U.S. by 15 companies.54
Measles vaccines (Pathogen type: RNA virus. Vaccine types:
live attenuated; [inactivated virus])
Two types of viral vaccines for measles were approved in theearly 1960s, one inactivated and the other a live attenuatedviral vaccine. The inactivated form was withdrawn from themarket due to low efficacy compared with the live attenuatedvaccine. The live attenuated vaccine was created through serial
passaging measles virus in chicken embryo tissue culture, andlater chicken embryo fibroblasts. 55 Historically, multiple
attenuated strains derived from a single seed virus (Edmonston
and Schwarz strains) were tested in Europe and the U.S. until
an improved less virulent version was identified in 1968
(Edmonston-Enders strain). In Asia, attenuated measles virus
from different seed isolates have been used (e.g., Leningrad 4
and 16 in Russia, Shanghai-190 in China, and CAM-70 in Japan).56 These live strains are manufactured using chicken embryos
and standard viral purification.
In 1971, the live attenuated measles vaccine was combined withmumps and rubella vaccines, creating a trivalent MMR vaccine(examples in the U.S. today are PRIORIX® and M-M-R II®). Morerecently, the varicella vaccine was combined with MMR,
creating the quadrivalent MMRV (live ProQuad® in the U.S.).57
Mumps Vaccines (Pathogen type: RNA virus. Vaccine type: live
attenuated, [inactivated])
As was the case with measles, the original mumps vaccine
contained an inactivated virus (approved in 1948); however,
was discontinued as more effective versions were developed.58
A superior mumps vaccine was licensed in 1967 in the U.S. The
improved vaccine contains a live attenuated virus (Jeril Lynn
strain), created by serial passaging in chicken eggs and chicken
embryo cell cultures.59 This live attenuated vaccine has beenpart of the MMR vaccine since 1971 and the monovalent vaccine
is no longer in production. Outside the U.S., several different
strains have been developed using similar methods and used
for broad vaccination (e.g., Leningrad-3 in Russia, Rubini strain
in Switzerland, Urabe in Japan, L-Zagreb in India).60
Rubella Vaccines (Pathogen type: RNA virus. Vaccine type:
live attenuated)
Unlike measles and mumps, early development attempts atinactivated rubella viral vaccines were unsuccessful and neverlicensed for use.61 The first rubella vaccine, which contained alive attenuated virus, was licensed in 1969. The original strain
was created by serial passaging the rubella virus in vervet
monkey kidney cells and duck embryo fibroblasts.62 This strain

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(HPV77, DE5) and another similar (Cendehill) were used until
1979 when a newer strain was developed (RA27/3, isolated froma human fetus kidney and serially passaged in lung fibroblast
cells). Outside the U.S., Japan and China each developed theirown attenuated strains of the rubella virus for inclusion into
regional vaccines in the 1970s.63
In 1971, a combined measles, mumps, and rubella (MMR)
vaccine was licensed for use in the United States. In 2005, a
combination measles, mumps, rubella, and varicella (MMRV)
vaccine was licensed.64
Varicella Zoster and Herpes Zoster Vaccines (Pathogen type:DNA virus. Vaccine type: live attenuated; protein VLP)
Although varicella zoster (chickenpox) and herpes zoster(shingles) are caused by the same virus, differences invaccination are required. Primary infection with varicella-zoster
virus (human herpesvirus 3, HHV-3), often in young children,causes varicella (often referred to as “Chickenpox”). Herpes
Zoster (often referred to as “Shingles”) is caused by thereactivation of the same varicella-zoster virus and isdifferentiated by the latency period in the central nervous
system (CNS) and reactivation in adults, as well its common
complication of postherpetic neuralgia (PHN). The herpes
zoster (shingles) vaccines are given only to adults, whereas thevaricella (chickenpox) vaccines are primarily given to children.
The original varicella-zoster live attenuated virus vaccine(Varivax®) was FDA approved in the 1990s for chickenpox. Other
monovalent versions today are also live attenuated vaccinesand based on the Oka strain (VARILRIX™, Okavax™).
Combination vaccines containing the varicella strains include
ProQuad™ (approved by FDA in 2005) and Priorix Tetra™
(approved outside the U.S., beginning with Australia in 2005).
Four different Oka varicella vaccines are used in China.65 Thereis also a monovalent MVA/06 strain developed in the 1990s in
South Korea (Suduvax®).66
The herpes zoster (shingles) vaccine Shingrix™ was licensed in2017 in the U.S. and globally thereafter. It is the only shingles
vaccine for U.S. adults, as Zostavax™ was removed in 2020.67
Shingrix™ is a protein VLP that incorporates a truncated, soluble
form of surface glycoprotein E (gE) into liposomes. The
liposomes are composed of dioleoyl phosphatidylcholine(DOPC) and cholesterol which mimic some of the lipid
characteristics of cell and viral membranes. A lipid-based
adjuvant (AS01B) containing monophosphoryl lipid A (MPL)and saponin is also included. The antigenic protein (gE) is
produced recombinantly in Chinese Hamster Ovary cells andpurified before inclusion into the liposomes.68

In the U.S., the anthrax vaccine adsorbed (AVA) was licensed
in 1970 for the first time. For 30 years, this single attenuatedstrain of B. anthracis was used to prepare cell-free filtrateadsorbed onto aluminum hydroxide.69 Its parental strain (Sterne
34F2), has been used globally for animal livestock vaccination
since the 1930s, and for a U.K. vaccine manufactured using
similar techniques.70 The vaccine’s final filtrate contains three
toxin components: protective antigen (PA, the most significant
antigen for immune response), lethal factor, and edemaforming protein. In the U.S. today, BioThrax®, based on these
original methods and formulated with aluminum andformaldehyde, remains the only licensed vaccine for anthrax
exposure.71 Prior to this, the Russians used an unrelated strain
to make a live attenuated anthrax vaccine, with and without
the addition of protective antigen, PA.72
Adenovirus Vaccines (Pathogen type: DNA virus. Vaccine
Types: live pathogen, inactivated)
The first adenovirus vaccine in the U.S. was an inactivated viral
vaccine (a bivalent mix of Ad4 and Ad7) grown in monkey
kidney cells and inactivated with formalin. This was usedprimarily for the military, but only for a few years in the early
1960s. Production of this inactivated vaccine was withdrawn
due to mutations and contaminations during propagation.73
A live (non-attenuated) viral Ad4 vaccine was licensed in the
1970s. It was produced in human diploid fibroblast strains as
the original kidney cells were not scalable. This was followed
years later with an Ad7 live vaccine. Both vaccines are given
simultaneously now in separate tablets to be swallowed.74
Although this live pathogen method can induce a brief, local
intestinal infection, it allows for a strong immune response that
protects against future respiratory exposure.
Tick-borne Encephalitis (TBE) Vaccines (Pathogen type: RNAvirus. Vaccine types: inactivated)
The first widely available TBE vaccine, FSME-IMMUN®, waslicensed in Europe beginning in the 1970s. It is an inactivatedviral vaccine made by propagating the Neudörfl TBE virus strain
in chick embryo fibroblast cells, inactivated with formaldehyde,
purified then adsorbed onto aluminum hydroxide. It only
became licensed in the U.S. in 2021 as TICOVAC™. In 1991,
Encepur® was licensed in Europe. Encepur® used a different
strain but was produced using the same production,
purification, and inactivation steps.75
Pneumococcal Vaccines (Pathogen type: bacteria. Vaccine
types: saccharide, saccharide-protein conjugate)

Anthrax Vaccines (Pathogen type: bacteria. Vaccine Types:
protein; live attenuated)

There are currently four pneumococcal vaccines approved in
the U.S. (PNEUMOVAX 23® (as of 1983), Prevnar 13® (2010),
Prevnar 20® (2021), VAXNEUVANCE® (2021)). 76 The firstpneumococcal vaccine contained purified capsular

BIO Industry Analysis

31polysaccharides from 23 individually grown serotypes ofStreptococcus pneumoniae (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V,
14, 18C, 19A, 19F and 23F). The conjugate vaccines, Prevnar 13®,
Prevnar 20®, and VAXNEUVANCE® (15 serotypes), are made by
growing each bacterial serotype in soy broth, purifying thepolysaccharides, converting to saccharides, then individuallylinking the saccharides to diphtheria CRM197 protein. Eachsaccharide-protein conjugate is then compounded to makethe final mix of protein-carbohydrate antigens, and aluminumis added as an adjuvant.
Prior to these vaccines, Prevnar®, a 7-valent PCV, was licensed
in 2000, but has since been replaced by the newer versions
listed above. Outside the U.S., these and similarly produced
vaccines are licensed (e.g., PCV-10 vaccines Synflorix™
and Pneumosil™).
Hepatitis B Vaccines (Pathogen type: DNA virus. Vaccine types:
protein subunit)
Prior to the advent of recombinant vaccines, plasma derived
hepatitis B vaccines were licensed in the early 1980s. These
contained the small surface antigen, HBsAgS, purified fromthe plasma of chronic HBsAg carriers. By the late 1980s, tworecombinant protein subunit vaccines were approved in the
U.S. For these recombinant vaccines, the small HBsAg isexpressed intracellularly in S. cerevisiae yeast, purified using
standard protein purification techniques, then adsorbed onto
aluminum. In 2017, a similar recombinant antigen product waslicensed, but this time expressed in Hansenula polymorphayeast and combined with a non-aluminum adjuvant. Morerecently, in 2021, a fourth recombinant hepatitis B vaccine
gained FDA approval. This latest vaccine differs from priorvaccines in that it includes all three surface antigen forms (small,
middle, and large). These proteins are expressed extracellularly
in Chinese hamster ovary cells, purified from the supernatant,then adsorbed onto aluminum.
Outside the U.S., there are more than 30 individual hepatitis
vaccines. Most of these are similar to those described above
with some using different yeast strains (e.g., pichia), mammaliancell lines (e.g., mouse c127), or longer forms of the HBsAg (i.e.,
Middle or Large). The latter change is significant in that
additional post translational modifications exist in those longer
forms (such as glycosylation and myristylation). Additionally,some of the manufactures outside the U.S. use different viral
subtypes. The adw subtype is used globally, while some ex-U.S.
vaccines contain the adr or ayw antigen.77
In addition to the four licensed hep. B vaccines in the U.S.,(Recombivax HB™, Engerix-B™, Heplisav-B™, and PreHevbrio™),
hep B vaccines have also been combined with DTaP, as
discussed above under the Diptheria vaccine description.

Haemophilus Influenza Type B (Hib) Vaccines (Pathogen type:bacteria. Vaccine type: saccharide-protein conjugate)
In the U.S. there are three monovalent vaccines for preventing
Haemophilus Influenza Type B (Hib): PedvaxHIB®, ActHIB®,
Hiberix®, which were approved in 1989, 1993, and 2009
respectively. PedavaxHib® is a carbohydrate-protein conjugate
vaccine that covalently links capsular polysaccharide purified
from the Haemophilus bacteria to an outer membrane protein
complex (OMPC) purified from Neisseria meningitidis
serogroup B (B11). ActHIB® and Hiberix™ are made by covalently
linking the purified capsular polysaccharide to purified tetanus
toxoid. Unlike PedvaxHIB®, ActHIB® and Hiberix™ do notcontain aluminum in the final product. ActHIB® and Hiberix™
use different strains of Hib (1482 and 20,752 respectively).78
Additionally, there are combination vaccines that include Hib.
In the U.S., there is a pentavalent vaccine (Pentacel®, FDA
approved in 2008) and a hexavalent vaccine (Vaxelis™, FDA
approved in 2018) combination vaccine given to children that
contains the pentavalent antigens plus the hepatitis B antigen.79
Influenza (flu) Vaccines (Pathogen type: RNA virus. Vaccine
types: inactivated; live-attenuated; protein)
Thirteen years after identifying the virus responsible for
influenza in 1933, the first flu vaccine was licensed for civilian
use in the U.S. This vaccine was a bivalent, inactivated viral
vaccine that included Type A and Type B strains of influenza
virus. It was made by growing both viral strains in embryonatedchicken eggs, followed by isolation of the virus by red blood
cell agglutination and centrifugation, then chemical inactivation
using formaldehyde.
Starting in 1973, seasonal variants of Type A and Type B wereincorporated into the inactivated flu vaccine, but in 1978, asecond Type A strain was introduced making the annual flu
vaccine trivalent.80 Since 2012, quadrivalent vaccines, which
include a second Type B strain in addition to the two Type A
strains, have been used globally. The 2023-2024 Northern
Hemisphere influenza vaccine formulation contains two TypeA strains (H1N1 2019 variant and H3N2 2021 variant) and two
Type B strains (2013 and 2021 regional variants).81 Traditional
egg propagation and inactivation methods can be found in
marketed vaccines such as Afluria® Quadrivalent, Fluad®
Quadrivalent and Fluzone® Quadrivalent.
Inactivated vaccines such as Flulaval®/Fluarix® Quadrivalent areinactivated using split technology. This splitting process uses
detergent to break the virus (grown in eggs) into separate
proteins, nucleic acids, and lipids, then removes the detergent
from the final product. The inactivated vaccines have fewer
adverse reactions as they are no longer intact virus particles.82

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Inactivated flu vaccines can also be made using cell culturesinstead of eggs, as of 2016. For example, Flucelvax®
Quadrivalent uses mammalian cell lines to propagate seasonalviral strains. As of 2021 in the U.S., all four seed virus strains
originate in mammalian cells and are delivered to
manufacturers by the CDC.83
FDA approved a second influenza vaccine type – live attenuated– in 2003. Originally developed as a trivalent seasonal vaccine
and the first flu vaccine delivered by intranasal mist, it is now
sold in the quadrivalent formulation (FluMist® Quadravalent,
Fluenz® Tetra). Outside the U.S., there are two additional live
attenuated flu vaccines marketed.
A third type of flu vaccine is the purified protein subunit vaccine,
approved for use in 2013 by the FDA. This was also originallytrivalent but contained only the hemagglutinin (HA) proteins fromeach seasonal strain, recombinantly generated in insect cells andpurified. A quadrivalent protein subunit formulation is now usedbroadly (Flublok® Quadrivalent).
The fourth type of influenza vaccine, marketed outside the U.S.,
is a virosomal vaccine which we categorize as protein-VLP. The
Inflexal® V vaccine is propagated in chicken eggs, HA andneuraminidase proteins purified and combined with a liposome
preparation. This creates a virus-like display of liposome
embedded proteins, hence the protein-VLP categorization.
Inflexal® V was first licensed in 1997.
Outside of seasonal flu vaccines, single strain vaccines havebeen produced for pandemics, such as the 2009 H1N1 swine
flu pandemic. The pandemic influenza vaccines weredeveloped leveraging all of the different technologies
described above. Companies that develop seasonal flu vaccines
often develop vaccines containing pandemic strains but reserve
them in bulk in order to be prepared in case of a pandemic.
T h i s w a s d o n e , fo r ex a m p l e fo r H 5 N 9 a n d o t h e r
pandemic strains.
Typhoid Fever Vaccines (Pathogen type: bacteria. Vaccine
type: inactivated; attenuated; conjugate)
The original vaccine for the prevention of Salmonella typhi
bacterial infection was a heat inactivated vaccine developedin the late 1800s. Inactivated vaccines for typhoid fever
improved in the 1950s and have since been replaced withnewer technologies.84 In the U.S., there are two typhoid vaccine
types: one is a purified polysaccharide antigen (Typhim Vi®)administered via injection (which is often referred to incorrectly
as an “inactivated” vaccine),the other is a live, attenuatedvaccine (Vivotif®), administered orally.85 Outside the U.S., there
are two injectable conjugate typhoid vaccines: Typbar-TCV®,
which links the Vi polysaccharide antigen to tetanus toxoid

BIO Industry Analysis

protein, and the other, TYPHIBEV®, conjugates the saccharide
to CRM197 protein.86
Japanese Encephalitis (JE) Vaccines (Pathogen type: RNAvirus. Vaccine type: inactivated; live attenuated)
In 1954, Japan licensed the first JE vaccine, an inactivated viral
vaccine using the Nakayama strain propagated in mousebrains.87 Cell-based production of JE vaccines eventuallyreplaced animal produced vaccines. In 1968, China licensed a
Beijing-3 strain manufactured in hamster kidney cells.88 Laterversions of inactivated JE vaccine were grown in Vero cells(derived from African Green Monkey kidney in 1962).
Currently, only one JE vaccine is licensed in the U.S. (Ixiaro®,2009) and it is manufactured using Vero cells, inactivated withformaldehyde and adsorbed onto aluminum hydroxide.89 Ixiaro®
uses an attenuated strain (SA14-14-2) created in China by serial
passaging the virus in hamster kidney cell cultures.
In 1988, the SA14-14-2 attenuated strain was licensed in China
as a live viral vaccine. It was later licensed to other countries.90
In 2010, a second live-attenuated vaccine, with very different
properties, was licensed in Australia. Unlike the original SA1414-2 attenuated vaccine, this latest JE vaccine, IMOJEV®, uses
yellow fever virus as the backbone RNA virus into which are
inserted the prM and E genes of SA14-14-2 JE vaccine. It is thus
referred to as a recombinant chimeric live attenuatedviral vaccine.
Hepatitis A Vaccines (Pathogen type: RNA virus. Vaccine type:
inactivated; live attenuated)
In the 1990s, the U.S. FDA granted licenses for two inactivatedviral vaccines for hepatitis A (Havrix™ and Vaqta®). For thesevaccines, the virus is propagated in human diploid cells,
purified, and inactivated with formalin. In 2001, a combination
vaccine incorporating the Havrix™ hepatitis A components
with inactivated hepatitis B vaccine was approved by the U.S.
FDA (Twinrix®).91
Outside the U.S., a live attenuated vaccine is licensed
throughout southeast Asia. The Chinese strains H2 and L-A-1
were derived from infected children and serial passaged incells to achieve attenuation. It is manufactured using human
diploid lung fibroblast cells.92
Additionally, there is a virosome vaccine marketed outside theU.S. (Epaxal®, approved in Europe in the mid-1990s).93 The
virosome vaccine differs from the inactive recombinantvaccines described above in that it encapsulates and embeds
the antigen protein into liposomes. These are grouped as VLPs
in Figure 3, as they are lipid/antigen nanoparticles roughly 150
nm in size that mimic the size and antigen presentation of the33

hepatitis B virus). Due to its protection and stability in the lipids,
the antigen protein can last longer in circulation.
Lyme Disease Vaccine (pathogen type: bacteria, Vaccine
types: protein)
Although there are no Lyme vaccines available today, there
was an FDA approved recombinant protein vaccine marketedfrom 1998-2001.94 This vaccine, LYMErix™, is comprised of theouter surface A (OspA) lipoprotein from Borrelia burgdorferi
expressed recombinantly in E. coli, purified, and adsorbed onto
aluminum hydroxide.
Meningococcal Disease Vaccines (Pathogen type: bacteria.
Vaccine types: carbohydrate-protein conjugate; saccharide)
The first meningococcal saccharide-protein conjugate vaccine(or “glyco-conjugate” for short), Menactra®, was licensed in the
U.S. in 2005. Glyco-conjugate vaccines have antigenic sugars(saccharides) bound to a protein substrate to help elicit a strongi m m u n e re s p o n s e . M e n a c t r a® i s m a d e u s i n g t h epolysaccharides from Neisseria meningitidis Groups A, C, Y and
W-135 conjugated to Corynebacterium diphtheriae Toxoid (DT).
Another glyco-conjugate vaccine, Menveo®, was licensed in2010 and is fused to the non-toxic Corynebacterium
diphtheriae CRM197 protein. In 2020, MenQuadfi® wasapproved in the U.S. It is similar to the above but conjugatedto tetanus toxoid (TT).95
There are currently two recombinant protein vaccines approvedin the U.S. that target meningococcal serogroup B. Bexsero®
contains adhesin A (NadA), heparin binding antigen (NHBA),
and factor H binding protein (fHbp) with outer membrane
vesicles (OMV) and aluminum.96 Vaccines based on OMVs weredeveloped more than 20 years ago against Neisseria
meningitidis serogroup B and have been used with somesuccess to control outbreaks of disease caused by serogroup
B meningococci.97 The second protein vaccine, Trumenba®,
contains two lipidated factor H binding proteins (fHbp from
subfamily A and B) produced in E. coli, purified and combinedwith aluminum in the final product.98
Prior to these five meningococcal vaccines, there was apolysaccharide-only vaccine (MPSV4) licensed in the U.S. in
1978. However, this vaccine is no longer available in the U.S.
Outside the U.S. multiple meningococcal vaccines are available,
such as MenAfriVac® (for serogroup A), and Nimenrix (forserogroups A, C, W, Y).
Rotaviral enteritis Vaccines (Pathogen type: DNA virus.
Vaccine type: live attenuated)
A live attenuated tetravalent vaccine (RotaShield™) wasapproved in 1998 but side effects forced it off the market after

one year. It used an attenuated rhesus monkey rotavirus
backbone with engineered/inserted human genes (for G1, G3,
G4).99 Attenuation of the rhesus monkey rotavirus was gainedby passaging in monkey kidney cells then in monkey lungfibroblast diploid cells.100
In the 2000s, live attenuated rotavirus vaccines were approved
and licensed worldwide. Both RotaTeq® and Rotarix™ containrotaviruses propagated and purified from Vero (African greenmonkey kidney) cells. Both are approved for the prevention ofrotavirus gastroenteritis caused by G1, G2, G3, G4, and G9
rotavirus types. However, Rotarix™ uses a single attenuatedviral strain (human G1/P8 type) while RotaTeq® contains fiveunique viruses.101
The RotaTeq® pentavalent vaccine takes advantage of thesegmented nature of the RNA viral genome. Rotavirus A, which
infects humans, has a two-strain classification system basedon two key surface glycoprotein proteins, VP7 (the G serotype)
and VP4 (the P serotype, which encodes the rotavirus Spikeprotein). There have been more than 30 VP7 G serotypes andmore than 50 VP4 P serotypes identified. Because the rotavirus
is segmented (it contains 11 RNA molecules), it can undergoswapping of these genes once two distinct serotypes enter acell.102 In human infections, P8 is most persistent and is often
found paired with G1, G3, G4, G9, G12. G2 is found paired with
P4, but other combinations of serotypes exist. 103 . The
pentavalent vaccine not only uses human genes, but bovine
as well, making for a complex mix of rotavirus serotypes. The
first four “reassortant” viruses in the vaccine are humanrotaviruses with bovine VP4 P7 genes that match with eitherof these four human VP7 versions: G1, G2, G3, G4. The fifthrotavirus contains human VP4 P8 gene andbovine VP7 G6 gene.104
Two attenuated rotavirus vaccines from India have been
licensed locally, although they are very similar to the vaccines
described above. For example, Rotasiil™ is a pentavalent vaccinewith bovine–human rotaviruses containing human G1, G2, G3,
G4, and G9. The other vaccine, Rotavac® is comprised of amonovalent attenuated human G9/P11 virus.105
Human Papillomavirus (HPV Vaccines) (Pathogen type: DNAvirus. Vaccine type: protein-VLP)
The first human papillomavirus (HPV) vaccine, Gardasil®, wasapproved in the U.S in 2006 for the prevention of cervical,
vulvar, vaginal and anal cancers caused by HPV Types 16 and18, and genital warts caused by Types 6 and 11.106 In 2009, a
bivalent vaccine, Cervarix®, was approved for Type 16 and 18.107
A nine-valent version of Gardasil®, which includes an additional
5 HPV Types (31, 33, 45, 52, 58), was approved in 2014 and has
replaced the older HPV vaccines in the U.S.108

34

BIO Industry Analysis

Each vaccine for HPV is comprised of recombinantly expressed
HPV capsid L1 proteins for each individual HPV Type. For
Gardasil®, yeast (Saccharomyces cerevisiae) is used for protein
expression. Yeast cells are disrupted and the L1 complexes selfassemble into virus-like particles (VLPs) that are subsequently
purified. Cervarix® uses insect cells (Trichoplusia ni) for
expression. After L1 protein purification, VLPs are formed andcombined with AS04 adjuvant.109 All three vaccine VLP preps
are adsorbed onto aluminum.
Dengue Vaccines (Pathogen type: RNA virus. Vaccine type:
live attenuated)
Early research and development of the dengue RNA virus
beginning in the 1920s was unsuccessful due to there being
four virus serotypes.110 Almost a century later, through the useof recombinant DNA technology, a live attenuated vaccine wasdeveloped and licensed.
Today there are two licensed live attenuated dengue vaccines,
Dengvaxia® licensed outside the U.S. starting in 2015 (in the
U.S. in 2019) and Qdenga® licensed outside the U.S. beginningin 2022 (U.S. BLA is under priority review with the FDA as ofthis writing). 111 The Dengavxia® vaccine is composed ofengineered chimeric viruses that have the prM and E genes
from four serotypes (DENV1,2,3,4) integrated into the backboneof yellow fever virus strain 17D.112 Qdenga® uses an attenuated
DENV-2 backbone for insertion of genes encoding prM and E
subunit proteins of Type 1,3,4 DENV serotypes.113
Enterovirus Vaccines (Pathogen type: RNA virus. Vaccine type:
inactivated virus)
In Asia, there have been four inactivated enterovirus A71
vaccines approved since 2015, the most recent of which wasapproved in 2023 in Taiwan.114
Ebola Vaccine (Pathogen type: DNA virus; Vaccine type:
recombinant live attenuated replicating virus)
In 2019, ERVEBO® was approved in the U.S. for the preventionof disease caused by Zaire ebolavirus. ERVEBO® is anengineered viral vaccine with the envelope glycoprotein genefrom ebolavirus (Zaire Kikwit strain) inserted into a vesicularstomatitis virus (VSV) backbone.115 VSV is a single-stranded
RNA virus that primarily infects animals but is attenuated upon
deletion of the native glycoprotein gene and replacement witha foreign glycoprotein gene.116 The virus is grown in Vero
(African green monkey kidney) cell cultures and purified fromthe growth medium.117
A prime/boost combination vaccine for Ebola was approvedby the European Medicines Agency (EMA) in 2020. Mvabea®
(MVA-BN Filo)/ Zabdeno® (Ad26.Zebov) uses a Modified

BIO Industry Analysis

Vaccinia Ankara vector encoding glycoproteins from the Ebola
Zaire, Ebola Sudan and Marburg virus. The second shot contains
Ad26 adenovirus encoding a protein from the Zaire strainof Ebola virus.
Malaria Vaccine (Pathogen type: parasite; Vaccine type: VLP)
A malaria virosomal protein subunit vaccine (Mosquirix™) was
prequalified by the WHO in 2022. The recombinant vaccine(also known as RTS,S) is made by expressing Plasmodium
falciparum circumsporozoite protein (regions R and T) fusedwith hepatitis B surface antigen (S), as well as being combinedwith hepatitis B surface antigen (S), from yeast cells(Saccharomyces cerevisiae).118 In addition to these proteins
forming VLPs, a lipid-based adjuvant (AS01) is added in the
final product.119 Another product has been recently approvedin Ghana, Nigeria, and Burkina Faso and recommended by
WHO SAGE for use, but this newer vaccine (R21) does notinclude free surface antigen and includes Matrix-M™ adjuvant.
SARS-CoV-2 Vaccines (pathogen type: RNA virus, Vaccine
Types: mRNA; protein VLP; rViral; inactivated)
In the U.S., two mRNA vaccines have received FDA approval(COMIRNATY® and Spikevax™) and two others (Nuvaxovid™
and Jcovden®) have received emergency use authorization(EUA). The mRNA vaccines code for the expression of the fulllength CoV-2 spike protein and are delivered as lipid
nanoparticles (LNPs) that encapsulate the mRNA. The two
vaccines under EUA are for the viral (adenovirus Ad26) vaccine
h a r b o r i n g t h e C oV - 2 s p i k e g e n e , a n d a s p i k eprotein VLP vaccine.
Outside of the U.S. there have been 10 unique vaccines
approved and 29 others that have been authorized for
COVID-19 since the start of the pandemic. Of these vaccines,
the largest portion of these are protein-based vaccines
containing Spike antigen, with 17 vaccines, and only one, aRussian made vaccine, receiving full approval (EpiVacCorona– approved in Turkmenistan). The 16 other vaccines have beenauthorized in multiple other countries: Spikogen® (authorizedin Iran) Coviccine® (authorized in China), SCB-219 (authorizedin China), Sinopharm NVSI (authorized in UAE), V-01 (authorizedin China), Zifivax™ (authorized in five countries), Abdala(authorized in six countries), Vidprevtyn™ Beta (authorized in
30 countries), CORBEVAX™ (authorized in India and Botswana),
IndoVac (authorized in Indonesia), Noora (authorized in Iran),Razai COV Pars® (authorized in Iran), SKYCovione™ (authorizedin South Korea), Bimervax® (authorized in the EU), ReCOV®
(authorized in Mongolia), and MVC-COV1901 (authorized in 3
countries). Two other vaccines are slightly different from thesingle purified protein examples above such as Soberana® 2(authorized in Iran) which it is a chemically conjugated SpikeTetanus Toxoid vaccine and COVIFENZ® (approved in Canada)35w h i c h u s e s a v i r u s- l i ke p a r t i c l e ( V L P ) fo r S p i keantigen presentation.
The second largest group of COVID-19 vaccines are viralbased vaccines with five fully approved vaccines:
CoronoaVac® (approved in China), Covaxin® (approved inIndia), Sinopharm BIBP (approved in four countries),
Sinopharm WIBP, (approved in China), and VLA2001(approved in the U.K.). Seven that have been authorized:
Covidful (authorized in China), COVIran Barekat (authorizedin Iran and Nicaragua), ERUCOV-VAC (authorized in Turkey),
FAKHRAVAC (authorized in Iran), KCONVAC™ (authorized in
China and Indonesia), KoviVac (authorized in three countries),and QazVac™ (authorized in Kazakhstan and Kyrgystan).
Of the remaining nine vaccines, one is a DNA vaccine(ZyCoV-D®, authorized in India) using plasmid DNA, three
RNA based vaccines: two being mRNA vaccines (AWcorna,
authorized in Indonesia and Stemirna, authorized in Laos),and one self-amplifying RNA (saRNA) vaccine (Gemcovac®,authorized in India), which is the first saRNA commercialized
in the world, and four rViral based vaccines: two using themodified chimpanzee adenoviruses (iNCOVACC®, authorizedin India, and Vaxzevria™, approved in five countries) and twoothers using other adenoviruses (Convidecia®, approved in
China and Sputnik V, approved in three countries).
iNCOVACC® is the only approved/authorized COVID-19
vaccine that is delivered intranasally.
Respiratory Syncytial Virus (RSV) Vaccines (Pathogen type:RNA virus; Vaccine type: protein subunit)
In early May 2023, the FDA approved the first RSV vaccine,
Arexvy. It is an engineered prefusion trimeric RSV F protein
expressed and purified from Chinese hamster ovary (CHO)
cells, and adjuvanted using AS01 with QS-21 Stimulon™.120 A
second RSV vaccine, Abrysvo™, wasapproved in late May
2023. Abrysvo™ is an unadjuvanted, bivalent RSV prefusion
F protein vaccine.121

Appendix II – Approved Prophylactic Antibodies
RabiesClostridioides difficile

Serum-derived antibodies for rabies have been used since
the early 1900s. Currently in the U.S. there are three human
Rabies Immune Globulin (RIG) products that protect
against rabies virus.122

In 2016, bezlotoxumab (Zinplava™) was approved by the FDA
to reduce recurrence of Clostridium difficile Infection.127
Bezlotoxumab binds to C. diff enterotoxin B.

RSVRespiGam®, a polyclonal immunoglobulin cocktail, wasapproved by the FDA in 1996 for the prevention of serious
RSV infection in children. 123 A monoclonal antibody,
palivizumab (Synagis®), was approved in 1998.124 It targets
the same RSV fusion protein that is part of the recently
approved protein vaccines. However, it binds to the postfusion conformation of the F protein. In July 2023, nirsevimab(Beyfortus), which binds to the pre-fusion conformation of
F protein, was approved for prevention of RSV in infants.

CMV
FDA approved Cytogam, CMV Immune Globulin (CMV-IGIV)
in 1998 for the prophylaxis of cytomegalovirus diseaseassociated with transplantation of kidney, lung, liver,pancreas, and heart.125

HIV
Although not a pathogen epitope binding antibody,
ibalizumab (Trogarzo™) was approved in 2018 for HIV
prevention. Rather than target HIV directly, the human CD4
is the target. This would be akin to an anti-ACE2
mAb for COVID-19.

COVID-19
During the COVID-19 pandemic, FDA authorized Evusheld™
(tixagevimab + cilgavimab) for pre-exposure prophylaxis.
However, in January 2023 authorization for use was rescinded
due to antigenic drift of new variants. Similarly, thebamlanivimab/etesevimab combination and the casirivimab/
imdevimab combination were authorized for post-exposure
prophylaxis of COVID-19 but are no longer authorized.128

Anthrax
Two monoclonal antibodies have been approved for theprophylaxis of inhaled anthrax. Raxibacumab (Abthrax®) wasapproved by the U.S. FDA in 2012, and obiltoxaximab(Anthim™) was approved in 2016.126

BIO Industry Analysis

37

Endnotes
			MMWR, April 2, 1999/Vol. 48/No. 12 Ten Great Public HealthAchievements—United States, 1900–1999. https://www.cdc.gov/
mmwr/preview/mmwrhtml/00056796.htm

12

			Vaccines, Plotkin and Mortimer, 1988.

3

			CDC website, accessed May 2023, https://www.cdc.gov/
vaccines/programs/vfc/protecting-children.html
			Human Papilloma Virus Vaccine Impact Monitoring Project(2020), https://www.cdc.gov/ncird/surveillance/hpvimpact/index.html

4			https://ourworldindata.org/reduction-of-cases-and-deaths-ofvaccine-preventable-diseases-in-the-us; Covid-19 data base on
the Israeli three dose data using mRNA vaccine pre-Omicron(N=843,208, with 758,118 receiving three mRNA doses, source:
https://www.timesofisrael.com/pre-omicron-israeli-researchpeople-50-who-got-3rd-shot-had-90-lower-death-rate/)		 Outside of these six company-sponsored programs, there is anotable academic program for Plasmodium vivax in Phase III
using viral vectors ChAd63 and MVA to recombinantly express
the Duffy-binding protein region II. Mimi M. Hou et al., “Vaccination with Plasmodium vivax Duffy-binding protein inhibits
parasite growth during controlled human malaria infection.” Sci.
Transl. Med.15, eadf1782(2023), https://www.science.org/
doi/10.1126/scitranslmed.adf1782

17

		 Moderna Announces Clinical and Program Updates at 4th
Vaccine Day, Moderna, (2023), https://investors.modernatx.com/
news/news-details/2023/Moderna-Announces-Clinical-and-Program-Updates-at-4th-Vaccines-Day/default.aspx

18

5

			This report focuses on company-sponsored clinical candidate
vaccines. Thus, preclinical and university developed vaccines are
not included. Furthermore, seasonal variants of established viral
vaccines are not included in the pipeline assessment (forexample, upcoming COVID-19 variant mRNA vaccines and the flu
2023/2024 vaccines are considered previously approved and notclinical candidates). Combination vaccines that combine
previously approved vaccines are not included.

19

6

		 This can also be viewed as passive when the recipient of theimmune benefit is a developing fetus receiving antibodies
generated by the active immune system of the mother after vaccination.

		 To calculate the level of private company venture capital
investment into infectious disease vaccines, we identify companies with a vaccine as the lead program and sum the total
venture funding each year. This can underestimate the venture
funding for some companies, as some companies have broader
pipelines outside their lead programs. Although most capital in asmall company will tend to be used for a lead asset, this is notalways the case.
		Vaccine company IPOs (2013-2022) raised $0.7 billion in the U.S.
and $2.5 billion Ex-U.S, from 20 transactions. For ex-U.S. IPOs the
majority ($1.9 billion) was raised by companies located in Asia.
Vaccine company secondary offerings (2013-2022) were $4.6
billion in the U.S. and $0.9 billion Ex-U.S., from 36 transactions.
The majority (84%) of secondary offerings were raised during the
COVID-19 pandemic, with one company receiving $1.9 billion(35% of all the funds raised in the recent decade)20

7

		 Variolation, the process of inoculation with a pathogen tobuilding immune defense for later infection by the same
pathogen, had been used in ancient times.

8

		 Biomedtracker and Pharmaprojects are database products from
Citeline, a Norstella company. The databases products can befound at https://www.citeline.com/en/products-services/
commercialization/biomedtracker and https://www.citeline.com/
en/products-services/clinical/pharmaprojects

9		 BIO COVID-19 Therapeutic Development Tracker, BIO, (2023)
https://www.bio.org/policy/human-health/vaccines-biodefense/
coronavirus/pipeline-tracker

10		 FDA Approvals & Clinical Development Pipeline, BIO, (2023),
https://www.bio.org/fda-approvals-clinical-development-pipeline

		 Oncology IPOs (2013-2022) raised $18.4 billion in the U.S. and$12.2 billion Ex-U.S. Oncology secondary offerings (2013-2022)
raised $46 billion in the U.S. and $14.2 billion Ex-U.S.

21

		The ESKAPE pathogens are six nosocomial pathogens thatexhibit multidrug resistance: Staphylococcus aureus, Klebsiellapneumoniae have ongoing clinical vaccine programs, butEnterococcus faecium, Acinetobacter baumannii, Pseudomonas
aeruginosa, and Enterobacter species do not.

22

23

https://www.fda.gov/news-events/press-announcements/
fda-approves-new-drug-prevent-rsv-babies-and-toddlers

24

Bloch, A B et al. “Health impact of measles vaccination in the
United States.” Pediatrics vol. 76,4 (1985): 524-32. https://pubmed.
ncbi.nlm.nih.gov/3931045/

25

Vaccination, Our World in Data (2023), https://ourworldindata.org/vaccination#not-every-child-who-should-be-vaccinated-is-vaccinated11		 Haranaka, Miwa et al. “Safety, tolerability, and immunogenicity ofa 21-valent pneumococcal conjugate vaccine, V116, in Japanese
healthy adults: A Phase I study.” Human vaccines & immunotherapeutics vol. 19,2 (2023), https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC10316726/

12

		 MacLennan, Calman Alexander et al. “The Shigella Vaccines
Pipeline.” Vaccines vol. 10,9 1376. 24 Aug. 2022, https://www.ncbi.
nlm.nih.gov/pmc/articles/PMC9504713/

		Esparza, José et al. “Early smallpox vaccine manufacturing in the
United States: Introduction of the “animal vaccine” in 1870,
establishment of “vaccine farms”, and the beginnings of thevaccine industry.” Vaccine vol. 38,30 (2020): 4773-4779.
doi:10.1016/j.vaccine.2020.05. /26

13

		 Zhu, Feng-Cai et al. “Evaluation of a recombinant five-antigen
Staphylococcus aureus vaccine: The randomized, single-centre
phase 1a/1b clinical trials.” Vaccine vol. 40,23 (2022): 3216-3227,
https://pubmed.ncbi.nlm.nih.gov/35473663/

		 Darin Carroll, et. Al, “Chasing Jenner’s Vaccine,” PLoS One, 6(8)(2011), https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152555/

27

14

		 Lyme Disease Vaccines 2023, Precision Vax LLC, (2023), https://www.precisionvaccinations.com/vaccines/lyme-disease-vaccines-2023

		Aysegul Nalca, Elizabeth Zumbrun, “ACAM2000™: The newsmallpox vaccine for United States Strategic National Stockpile,”
Drug Des Devel Ther., 4: 71-79 (2010), https://www.ncbi.nlm.nih.
gov/pmc/articles/PMC2880337/

28

15

		 The AS01B-4 adjuvant is a liposomal combination of 3-O-desacyl-4-monophosphoryl lipid A (MPL) from Salmonella minnesota
and a saponin molecule (QS-21) from plant extract of
Quillaja saponaria.

16

		Vaccine Timeline, History of Vaccines, https://historyofvaccines.
org/history/vaccine-timeline/overview

29

		A. Volz, G. Sutter, “Modified Vaccina Virus Ankara,” Adv Virus Res,
97: 187-243 (2016), https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC7112317/; Mark Suter, et. Al. “Modified Vaccinia Ankara
Strains,” Vaccine, 27(52): 7442-50 (2009), https://pubmed.ncbi.nlm.
nih.gov/19539582/

30

31		 Kenner, Julie et al. “LC16m8: an attenuated smallpox vaccine.”
Vaccine vol. 24,47-48 (2006), https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC7115618/

38

BIO Industry Analysis

		JYNNEOS Smallpox Mpox Vaccine, Precision Vaccinations (2023),
https://www.precisionvaccinations.com/vaccines/jynneos-smallpox-mpox-vaccine

49

		Smith, K. Louis Pasteur, the Father of Immunology? Front
Immunology v3 (68) (2012); Wu, X., et. al. From brain passage tocell adaptation: The road of human rabies vaccine development.
Expert Rev Vaccines (2011)

50

32

33

		Human Vaccines, World health Organization, 2023, https://web.
archive.org/web/20121103135631/http://www.who.int/rabies/
vaccines/human_vaccines/en/index.html

		The original production of IPV involved propagating polio virus inmonkey kidney cells, followed by inactivation using formaldehyde.
		Jonas Salk developed the first inactivated polio vaccine for polio,
while Albert Sabin is credited with making the live-attenuatedoral polio vaccine.

		 Baicus, A, “History of polio vaccination.” World J Virol. 1(4): 108–114(2012). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782271

51

34

		Vaccines Licensed for Use in the United States, U.S. Food & Drug
Administration, (2023), https://www.fda.gov/vaccines-blood-biologics/vaccines/vaccines-licensed-use-united-states

52

		Vaccines Licensed for Use in the United States, U.S. Food & Drug
Administration, (2023), https://www.fda.gov/vaccines-blood-biologics/vaccines/vaccines-licensed-use-united-states [Somerabies vaccines are inactivated by propiolactone]

53		Baldauf, Keegan J et al. “Cholera toxin B: one subunit with many
pharmaceutical applications.” Toxins vol. 7,3 974-96. 20 Mar. 2015,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379537/; Hanif
Shaikh, et. Al. “Current and future cholera vaccines,” Vaccine 38(1):A118-A126 (2020), https://www.sciencedirect.com/science/article/
pii/S0264410X19316536

54

35

		Epidemiology of Prevention of Vaccine-Preventable Diseases,
Measles (2021), https://www.cdc.gov/vaccines/pubs/pinkbook/meas.html; Griffin, Diane E. “Measles Vaccine.” Viral immunology
vol. 31,2 (2018): 86-95, https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC5863094/

36

		EvaluatePharma Database (2023), https://www.evaluate.com/
products-services/evaluate-omnium

		Human Vaccines, World health Organization, 2023, https://web.
archive.org/web/20121103135631/http://www.who.int/rabies/
vaccines/human_vaccines/en/index.html; Vaccines Licensed for
Use in the United States, U.S. Food & Drug Administration, (2023),
https://www.fda.gov/vaccines-blood-biologics/vaccines/
vaccines-licensed-use-united-states;Centers for Disease Control
and Prevention, List of Vaccines Used in the United States (2018),
https://www.cdc.gov/vaccines/vpd/vaccines-list.html

55

		 Sunheang Shin, et. Al. “Oral Vaccines Against Cholera,” Clinical
Infectious Diseases Vol. 52(11), 1343-1349 (2011), https://academic.
oup.com/cid/article/52/11/1343/406640; Odevall, Lina et al. “The
Euvichol story - Development and licensure of a safe, effective
and affordable oral cholera vaccine through global public private
partnerships.” Vaccine vol. 36,45 (2018), https://www.ncbi.nlm.nih.
gov/pmc/articles/PMC6203809/

37

		Vaxchora, U.S. FDA Food & Drug, December 2022, https://www.
fda.gov/vaccines-blood-biologics/vaccines/vaxchora; Saluja,
Tarun et al. “An overview of VaxchoraTM, a live attenuated oralcholera vaccine.” Human vaccines & immunotherapeutics vol. 16,1
(2020), https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012186

38

56

		Luca, Simona, and Traian Mihaescu. “History of BCG Vaccine.”
Maedica vol. 8,1 (2013), https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC3749764/

39

		Angelidou, Asimenia et al. “Licensed Bacille Calmette-Guérin(BCG) formulations differ markedly in bacterial viability, RNAcontent and innate immune activation.” Vaccine vol. 38,9 (2020),
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556328/

40

		 Two of the infectious diseases listed in Figure 1 do not havevaccines that target the pathogen or its connected subunits
directly, but rather its secreted toxins. The first being Diphtheria
toxin, and the second Tetanus toxoid protein.

		 Merck, News release (2023), https://www.merck.com/news/
us-fda-approves-intramuscular-administration-for-mercksmmrv-family-of-vaccines-m-m-rii-measles-mumps-and-rubellavirus-vaccine-live-varivax-varicella-virus-vaccinelive-and-proquad

5741

		Diphtheria, History of Vaccines, (2023), https://historyofvaccines.
org/history/diphtheria/timeline42

		Ammour, Yulia, et al. “The Susceptibility of Human Melanoma
Cells to Infection with the Leningrad-16 Vaccine Strain of Measles
Virus” Viruses 12, no. 2: 173 (2020), https://www.mdpi.com/19994915/12/2/173; Bettina Bankamp, et. Al., “Genetic Characterizationof Measles Vaccine Strains,” The Journal of Infectious Diseases,
Vol. 204(1) (2011), Pages S533–S548, https://academic.oup.com/
jid/article/204/suppl_1/S533/2192942; Griffin, Diane E. “Measles
Vaccine.” Viral immunology vol. 31,2 (2018): 86-95, https://www.
ncbi.nlm.nih.gov/pmc/articles/PMC5863094/

		Elliot Gardner, Tracing the story of mumps, Pharmaceutical
Technology, (2018), https://www.pharmaceutical-technology.
com/features/tracing-story-mumps-timeline/

58

59

		Dave Roos, How a New Vaccine Was Developed in Record Timein the 1960s, History, (2021), https://www.history.com/news/
mumps-vaccine-world-war-ii

		Vaccines Licensed for Use in the United States, U.S. Food & Drug
Administration, (2023), https://www.fda.gov/vaccines-blood-biologics/vaccines/vaccines-licensed-use-united-states

60

		The adult formulation for combinations is different than pediatricformulations, thus use a different acronym: Tdap versus
DTaP for pediatric.

61

		Collins, N. et. al. Live Attenuated Yellow Fever 17D Vaccine: A
Legacy Vaccine Still Controlling Outbreaks In Modern Day. Curr
Infect Dis Rep. v19 (3) (2017)

62

43

		The Mumps Vaccine, WHO, (1998), https://web.archive.org/
web/20060423093835/http://www.who.int/vaccines-diseases/
diseases/mumps_vaccine.shtml

44

45

		Gomez, P., et. al. Vaccine manufacturing. Vaccines (Section one:
General aspects of vaccination) Ch.4, p44–57. (2013)46

		 Cherry, J. Pertussis: Challenges Today and for the Future. PLoS
Pathogen v9 (7) (2013)47

		Human Vaccines, World health Organization, 2023, https://web.
archive.org/web/20121103135631/http://www.who.int/rabies/
vaccines/human_vaccines/en/index.html; Vaccines Licensed for
Use in the United States, U.S. Food & Drug Administration, (2023),
https://www.fda.gov/vaccines-blood-biologics/vaccines/
vaccines-licensed-use-united-states

48

BIO Industry Analysis

		 Best, J M. “Rubella vaccines: past, present and future.” Epidemiology and infection vol. 107,1 (1991): 17-30, https://www.ncbi.nlm.nih.
gov/pmc/articles/PMC2272034/?page=1
		The Mumps Vaccine, WHO, (1998), https://web.archive.org/
web/20060423093835/http://www.who.int/vaccines-diseases/
diseases/mumps_vaccine.shtml
		Dave Roos, How a New Vaccine Was Developed in Record Timein the 1960s, History, (2021), https://www.history.com/news/
mumps-vaccine-world-war-ii

63

		Rubella, Centers for Disease Control and Prevention, (2021),
https://www.cdc.gov/vaccines/pubs/pinkbook/rubella.html

6465

		Anne A Gershon, et. Al., “Live Attenuated Varicella Vaccine,” The
Journal of Infectious Diseases Vol.224(4) (2021), S387–S397, https://academic.oup.com/jid/article/224/Supplement_4/S387/6378094

39

66

67

		Ui Yoon Choi, et. Al. “Immunogenicity and safety profiles of a new
MAV/06 strain varicella vaccine in healthy children,” Vaccine.
Vol.39(12) (2021), 1758-1764, https://www.sciencedirect.com/
science/article/pii/S0264410X21001614; Jeong Seon Jeon, et. Al.,
“Analysis of single nucleotide polymorphism among Varicella-Zoster Virus,” Virology, Vol. 496 (2016), 277-286, https://www.
sciencedirect.com/science/article/pii/S0042682216301581

		 Shingles Vaccination, Centers for Disease Control and Prevention,(2023), https://www.cdc.gov/vaccines/vpd/shingles/public/
shingrix/index.html
		Shingrix Website, (2023), https://www.shingrixhcp.com

68
69

		Scorpio, A., “Anthrax vaccines: Pasteur to the present,” Cell. Mol.
Life Sci. 63 (2006), 2237–2248; Joellenbeck LM, et. Al. “The Anthrax
Vaccine,” National Academies Press (US) , Vol. 7 (2002), https://www.ncbi.nlm.nih.gov/books/NBK220526/table/ttt00024/?report=objectonly; The original U.S. strain is avirulent, nonencapsulated V770-NP1-R (missing a virulence plasmid, pXO1+ / pXO2–,
thus unable to produce a protective polysaccharide capsule)derived from the Sterne strain. The United Kingdom vaccine uses
34F2 Sterne strain. The Russian attenuated strain is LAV STI-1, isgenetically different from the Sterne strain. (Keim P, et. al.
Multiple-locus variable-number tandem repeat analysis reveals
genetic relationships within Bacillus anthracis. J Bacteriol. 182(2000), p2928–2936)
		Anthrax Sterne strain (34F2) of Bacillus anthracis, Centers for
Disease Control and Prevention, (2022), https://www.cdc.gov/
anthrax/resources/anthrax-sterne-strain.html

		Theone C. Kon, et. Al. “Influenza Vaccine Manufacturing.” PLOS
One, (2016), https://journals.plos.org/plosone/article?id=10.1371/
journal.pone.0150700

82

		How Influenza (Flu) Vaccines Are Made, Centers for Disease
Control and Prevention, (2022), https://www.cdc.gov/flu/prevent/
how-fluvaccine-made.htm

83		Bockemühl J. Die Typhus-Schutzimpfung gestern und heute[Typhoid vaccination yesterday and today]. Immun Infekt. 1983
Jan;11(1):16-22. German, https://pubmed.ncbi.nlm.
nih.gov/6341210/

84

		Meningococcal Vaccination, Centers for Disease Control andPrevention, (2021), https://www.cdc.gov/vaccines/vpd/mening/
public/index.html; Typhoid VI Package Insert, U.S. Food & Drug
Administration, (2020), https://www.fda.gov/media/75993/
download; Vivotif Package Insert, Emergent Biosolutions, (2020),
https://www.emergentbiosolutions.com/wp-content/uploads/2022/01/Vivotif-US-Prescribing-Information.pdf

85

		Typbar TCV Package Insert, Bharat Biotech, (2023) https://bharatbiotech.com/images/typbartcv/Typbar-TCV-Package-Insert.pdf; Typhibev, WHO, (2020), https://extranet.who.int/pqweb/
content/typhibev%C2%AE-086		 Vijaya Satchidanandam, “Japanese Encephalitis Vaccines.” Current
Treatment Options Infectious Disease 12 (2020): 375-386, https://link.springer.com/article/10.1007/s40506-020-00242-5

87

70

		 BioThrax Package Insert, U.S. Food & Drug Administration, (2015),
https://www.fda.gov/media/71954/download

		Schiøler, K L et al. “Vaccines for preventing Japanese encephalitis.”
The Cochrane database of systematic reviews vol. 2007(3), (2007),https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532601/

88

71

		 Feodorova, Valentina A et al. “Russian vaccines against especially
dangerous bacterial pathogens.” Emerging microbes & infections
vol. 3,12 (2014), https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC4317636/; Chitlaru, T., et. al. “Next-Generation Bacillus
anthracis Live Attenuated Spore Vaccine,” Nature, Scientific
Reports. 18908 (2016)

		Ixiaro, U.S. Food & Drug Administration, (2019), https://www.fda.
gov/vaccines-blood-biologics/vaccines/ixiaro

8972

		 Gray, Gregory C., and Dean D. Erdman. “Adenovirus Vaccines.”
Plotkin’s Vaccines (2018): 121–133, https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC7151885/

73

		Kitchener, S. “The rise and fall of Japanese Encephalitis vaccination in the ADF – Where to now?” Journal of Military and
Veteran’s Health. 16 (3), (2021) https://jmvh.org/article/the-riseand-fall-of-japanese-encephalitis-vaccination-in-theadf-where-to-now/90		 R. Monian Klevens, et. Al. “Hepatitis A Virus.” Antimicrobe, (2023),
http://www.antimicrobe.org/v05.asp

91

		Live attenuated hepatitis A vaccine, WHO, (2010), https://www.
who.int/groups/global-advisory-committee-on-vaccine-safety/
topics/hepatitis-a#cms

92

		 See note 54 above; (sequencing of the original Wyeth vaccine
strains, which Teva uses today, did not reveal any attenuating mutations)93

		 Barret, P. “History of TBE vaccines.” Vaccine. 21 (1) (2003: pS41-S49;
Ticovac, U.S. Food & Drug Administration, (2021), https://www.
fda.gov/vaccines-blood-biologics/ticovac

94

74

		Krasnopolsky, Y. et. al. Licensed liposomal vaccines and adjuvantsin the antigen delivery system. BioTechnologia 103(4)(2022): 409–423

75

		 Human Vaccines, World health Organization, 2023, https://web.
archive.org/web/20121103135631/http://www.who.int/rabies/
vaccines/human_vaccines/en/index.html; Vaccines Licensed for
Use in the United States, U.S. Food & Drug Administration, (2023),
https://www.fda.gov/vaccines-blood-biologics/vaccines/
vaccines-licensed-use-united-states

		Nigrovic, L E, and K M Thompson. “The Lyme vaccine: a cautionary tale.” Epidemiology and infection vol. 135,1 (2007): 1-8, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2870557

76

		 Romano, L. et. al. “Hepatitis B vaccination.” Hum Vaccin Immunother. 11(1) (2015): 53–57

77

78

		 Haemophilus influenzae type b (Hib) Vaccine, Centers for Disease
Control and Prevention, (2022), https://www.cdc.gov/vaccinesafety/vaccines/hib-vaccine.html

		 Vaccines Licensed for Use in the United States, U.S. Food & Drug
Administration, (2023), https://www.fda.gov/vaccines-blood-biologics/vaccines/vaccines-licensed-use-united-states

79		Claude Hannoun, “The Evolving History of Influenza Viruses andInfluenza Vaccines.” Expert Rev Vaccines, 12(9) (2013): 1085-1094,
https://www.medscape.com/viewarticle/812621

80

		 Influenza Vaccine for the 2023-2024 Season, U.S. Food & Drug
Administration, (2023), https://www.fda.gov/vaccines-blood-biologics/lot-release/influenza-vaccine-2023-2024-season#:~:text=For%20trivalent%20influenza%20vaccines%20for,for%20the%20
quadrivalent%20vaccines%20be 1

81

		About Meningococcal Vaccines, Centers for Disease Control andPreventions, (2022), https://www.cdc.gov/vaccines/vpd/mening/
hcp/about-vaccine.html

95		Bexsero, U.S. Food & Drug Administration, (2023), https://www.
fda.gov/vaccines-blood-biologics/vaccines/bexsero

96

		 Acevedo Reinaldo, et. al. “Bacterial Outer Membrane Vesicles andVaccine Applications.” Frontiers in Immunology Vol. 5 (2014),
https://www.frontiersin.org/articles/10.3389/
fimmu.2014.00121/full.

97

		Trumenba, U.S. Food & Drug Administration, (2021), https://www.
fda.gov/vaccines-blood-biologics/vaccines/trumenba

98		Greenberg, Harry B, and Mary K Estes. “Rotaviruses: from
pathogenesis to vaccination.” Gastroenterology vol. 136,6 (2009):
1939-51, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690811/

99

		Kapikian, A Z et al. “Efficacy of a quadrivalent rhesus rotavirus-based human rotavirus vaccine aimed at preventing severe
rotavirus diarrhea in infants and young children.” The Journal of
infectious diseases vol. 174 Suppl 1 (1996): S65-72, https://pubmed.
ncbi.nlm.nih.gov/8752293/

100

40

BIO Industry Analysis

		Dennehy, Penelope H. “Rotavirus vaccines: an overview.” Clinicalmicrobiology reviews vol. 21,1 (2008): 198-208, https://www.ncbi.
nlm.nih.gov/pmc/articles/PMC2223838/; Juana Agnel, et. Al.
“Rotavirus Vaccines: recent developments and future considerations.” Nature Reviews Microbiology Vol.5 (2007): 529-539,
https://www.nature.com/articles/nrmicro1692

101

		Varghese, Tintu et al. “Understanding Rotavirus Vaccine Efficacy
and Effectiveness in Countries with High Child Mortality.”
Vaccines vol.10(3) (2022): 346, https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC8948967/

102

		Vijaykrishna, Dhanasekaran et al. “RNA Virus Reassortment: An
Evolutionary Mechanism for Host Jumps and Immune Evasion.”
PLoS pathogens vol. 11,7 (2015), https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC4497687/; Manouana, Gédéon Prince et al.
“Molecular surveillance and genetic divergence of rotavirus A
antigenic epitopes in Gabonese children with acute gastroenteritis.” EBioMedicine vol. 73 (2021): 103648 https://www.ncbi.nlm.nih.
gov/pmc/articles/PMC8551588/

		Morozov, Igor et al. “High dose of vesicular stomatitis virus-vectored Ebola virus vaccine causes vesicular disease in swine
without horizontal transmission.” Emerging microbes & infections
vol. 10,1 (2021): 651-663, https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC8023602/

116

		Fathi, Anahita et al. “Recombinant vesicular stomatitis virus vector
vaccines for WHO blueprint priority pathogens.” Human vaccines& immunotherapeutics vol. 15,10 (2019): 2269-2285, https://www.
ncbi.nlm.nih.gov/pmc/articles/PMC6816421/

117

		WHO grants prequalification to GSK’s Mosqurix, GSK, (2022),
https://www.gsk.com/en-gb/media/press-releases/who-grantsprequalification-to-gsk-s-mosquirix-the-first-and-only-approved-malaria-vaccine/

118

103

		Mosquirix: Opinion on medicine for use outside EU, European
Medicines Agency, (2015), https://www.ema.europa.eu/en/
opinion-medicine-use-outside-EU/human/mosquirix

119		Langley, Joanne M et al. “A Randomized, Controlled, Observer-Blinded Phase 1 Study of the Safety and Immunogenicity of a
Respiratory Syncytial Virus Vaccine With or Without Alum
Adjuvant.” The Journal of infectious diseases vol. 215,1 (2017):
24-33, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225248/

120

		RotaTeq, U.S. Food & Drug Administration, (2020), https://www.
fda.gov/vaccines-blood-biologics/vaccines/rotateq

104

		Varghese, T. et. al. “Understanding Rotavirus Vaccine Efficacy andEffectiveness in Countries with High Child Mortality.” Vaccines 10(3) (2022)

105

		Gardasil, U.S. Food & Drug Administration, (2023), https://www.
fda.gov/vaccines-blood-biologics/vaccines/gardasil

106

		Cervarix, U.S. Food & Drug Administration, (2019), https://www.
fda.gov/vaccines-blood-biologics/vaccines/cervarix

107

		U.S. Food & Drug Administration, (2014), https://web.archive.org/
web/20150110233107/https://www.fda.gov/NewsEvents/
Newsroom/PressAnnouncements/ucm426485.htm; Gardasil 9,
U.S. Food & Drug Administration, (2023), https://www.fda.gov/
vaccines-blood-biologics/vaccines/gardasil-9

		U.S. FDA Approves ABRYSVI TM, Pfizer’s Vaccine for the Prevention of Respiratory Syncytial Virus (RSV) in Older Adults, Pfizer,(2023), https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-abrysvotm-pfizersvaccine-prevention

121

		FDA Approves KedRAB, Drugs.com, (2017), https://www.drugs.
com/newdrugs/fda-approves-kedrab-rabies-immune-globulin-human-post-exposure-prophylaxis-rabies-infection-4584.html

122

108

		Deschuyteneer, Michel et al. “Molecular and structural characterization of the L1 virus-like particles that are used as vaccine
antigens in Cervarix™, the AS04-adjuvanted HPV-16 and -18
cervical cancer vaccine.” Human vaccines vol. 6,5 (2010): 407-19,
https://pubmed.ncbi.nlm.nih.gov/20953154/

		Wasserman, Richard L et al. “RI-002, an intravenous immunoglobulin containing high titer neutralizing antibody to RSV andother respiratory viruses for use in primary immunodeficiency
disease and other immune compromised populations.” Expert
review of clinical immunology vol. 13,12 (2017): 1107-1119, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103707/

123

109

		McArthur, Monica A et al. “Dengue vaccines: recent developments, ongoing challenges and current candidates.” Expert
review of vaccines vol. 12,8 (2013): 933-53, https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC3773977/

		Pantaleo, G., et al. “Antibodies to combat viral infections.” Nat Rev
Drug Discovery 21 (2022): 676-696, https://www.nature.com/
articles/s41573-022-00495-3

124

110

		Dengvaxia, U.S. Food & Drug Administration, (2023), https://www.
fda.gov/vaccines-blood-biologics/dengvaxia; Kevin Dunleavy,
JPM23: Takeda taps contract manufacturer for dengue vaccine
launch as it works to grow capacity, Fierce Pharma, (2023), https://www.fiercepharma.com/manufacturing/takeda-prepares-launch-dengue-vaccine-it-expands-manufacturing-capacity

		Selected Important Safety Information for Cytogam, Cytogam.
com (2023), https://cytogam.com/

125

		Products Approved for Anthrax, U.S. Food & Drug Administration(2019), https://www.fda.gov/drugs/bioterrorism-and-drug-preparedness/products-approved-anthrax

126

111

		Bezlotoxumab, Wikipedia (2023), https://en.wikipedia.org/
wiki/Bezlotoxumab

127

128

		Thomas, Stephen J, and In-Kyu Yoon. “A review of Dengvaxia®:
development to deployment.” Human vaccines & immunotherapeutics vol. 15,10 (2019): 2295-2314, https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC6816420/

112

		Tekada TAK-003 Presentation, Center for Disease Control andPrevention, (2023), https://www.cdc.gov/vaccines/acip/meetings/
downloads/slides-2023-02/slides-02-23/dengue02-biswal-508.pdf

113		Kao Shih-ching, FDA approves first local-made vaccine for EV-71,
Taipei Times, (2023), https://www.taipeitimes.com/News/biz/archives/2023/01/31/2003793393; Li, Mei-Ling et al. “Enterovirus
A71 Vaccines.” Vaccines vol. 9,3 199. 27 Feb. 2021, www.ncbi.nlm.
nih.gov/pmc/articles/PMC7997495

114

		Ervebo, U.S. Food & Drug Administration, (2023), https://www.
fda.gov/vaccines-blood-biologics/ervebo; Monath, Thomas P etal. “rVSVΔG-ZEBOV-GP (also designated V920) recombinantvesicular stomatitis virus pseudotyped with Ebola Zaire Glycoprotein: Standardized template with key considerations for a risk/
benefit assessment.” Vaccine: X vol. 1 100009. 29 Jan. 2019, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668225/

115

BIO Industry Analysis

41

Emergency Use Authorization (EUA) for the Treatment or
Post-Exposure Prophylaxis of COVID-19, Lilly, (2023) https://www.
covid19.lilly.com/bam-ete, https://www.cms.gov/monoclona

www.bio.org/iareports

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BIO Industry Analysis